Up-regulation of SLC7A11/xCT creates a vulnerability to selenocystine-induced cytotoxicity.

The SLC7A11/xCT cystine and glutamate antiporter has emerged as an attractive target for cancer therapy due to its selective overexpression in multiple cancers and its role in preventing ferroptosis. Utilizing pharmacological and genetic approaches in hepatocellular carcinoma cell lines, we demonstrate that overexpression of SLC7A11 engenders hypersensitivity towards l-selenocystine, a naturally occurring diselenide that bears close structural similarity to l-cystine. We find that the abundance of SLC7A11 positively correlates with sensitivity to l-selenocystine, but surprisingly, not to Erastin, an inhibitor of SLC7A11 activity. Our data indicate that SLC7A11 acts as a transport channel for l-selenocystine, which preferentially incites acute oxidative stress and damage eventuating to cell death in cells that highly express SLC7A11. Hence, our findings raise the prospect of l-selenocystine administration as a novel strategy for targeting cancers that up-regulate SLC7A11 expression.

Genetic Ablation of LAT1 Inhibits Growth of Liver Cancer Cells and Downregulates mTORC1 Signaling.

Through a comprehensive analysis of the gene expression and dependency in HCC patients and cell lines, LAT1 was identified as the top amino acid transporter candidate supporting HCC tumorigenesis. To assess the suitability of LAT1 as a HCC therapeutic target, we used CRISPR/Cas9 to knockout (KO) LAT1 in the epithelial HCC cell line, Huh7. Knockout of LAT1 diminished its branched chain amino acid (BCAA) transport activity and significantly reduced cell proliferation in Huh7. Consistent with in vitro studies, LAT1 ablation led to suppression of tumor growth in a xenograft model. To elucidate the mechanism underlying the observed inhibition of cell proliferation upon LAT1 KO, we performed RNA-sequencing analysis and investigated the changes in the mTORC1 signaling pathway. LAT1 ablation resulted in a notable reduction in phosphorylation of p70S6K, a downstream target of mTORC1, as well as its substrate S6RP. This reduced cell proliferation and mTORC1 activity were rescued when LAT1 was overexpressed. These findings imply an essential role of LAT1 for maintenance of tumor cell growth and additional therapeutic angles against liver cancer.

Photoacoustic Tomography Appearance of Fat Necrosis: A First-in-Human Demonstration of Biochemical Signatures along with Histological Correlation.

A 50-year-old woman with no past medical history presented with a left anterior chest wall mass that was clinically soft, mobile, and non-tender. A targeted ultrasound (US) showed findings suggestive of a lipoma. However, focal "mass-like" nodules seen within the inferior portion suggested malignant transformation of a lipomatous lesion called for cross sectional imaging, such as MRI or invasive biopsy or excision for histological confirmation. A T1-weighted image demonstrated a large lipoma that has a central fat-containing region surrounded by an irregular hypointense rim in the inferior portion, confirming the benignity of the lipoma. An ultrasound-guided photoacoustic imaging (PA) of the excised specimen to derive the biochemical distribution demonstrated the "mass-like" hypoechoic regions on US as fat-containing, suggestive of benignity of lesion, rather than fat-replacing suggestive of malignancy. The case showed the potential of PA as an adjunct to US in improving the diagnostic confidence in lesion characterization.

MicroRNAs as Potential Biomarkers in the Differential Diagnosis of Lipomatous Tumors and Their Mimics.

Adipocytic tumors are the most common subtype of soft tissue tumors. In current clinical practice, distinguishing benign lipomas from well-differentiated liposarcomas (WDLPS), as well as dedifferentiated liposarcomas (DDLPS) from their morphologic mimics, remains a significant diagnostic challenge. This is especially so when examining small biopsy samples and without the aid of additional ancillary tests. Recognizing the important role that microRNAs (miRNAs) play in tumorigenesis and their potential utility in tumor classification, we analyzed routine clinical tissue samples of benign and malignant lipomatous tumors, as well as other sarcoma mimics, to identify distinguishing miRNA-based signatures that can aid in the differential diagnosis of these entities. We discovered a 6-miRNA signature that separated lipomas from WDLPS with high confidence (AUC of 0.963), as well as a separate 6-miRNA signature that distinguished DDLPS from their more aggressive histologic mimics (AUC of 0.740). Functional enrichment analysis unveiled possible mechanistic involvement of these predictive miRNAs in adipocytic cancer-related biological processes and pathways such as PI3K/AKT/mTOR and MAPK signaling, further supporting the relevance of these miRNAs as biomarkers for adipocytic tumors. Our results demonstrate that miRNA expression profiling may potentially be used as an adjunctive tool for the diagnosis of benign and malignant adipocytic tumors. Further validation studies are warranted.

Biochemical "decoding" of breast ultrasound images with optoacoustic tomography fusion: First-in-human display of lipid and collagen signals on breast ultrasound.

To date, studies which utilized ultrasound (US) and optoacoustic tomography (OT) fusion (US-OT) in biochemical differentiation of malignant and benign breast conditions have relied on limited biochemical data such as oxyhaemoglobin (OH) and deoxyhaemoglobin (DH) only. There has been no data of the largest biochemical components of breast fibroglandular tissue: lipid and collagen. Here, the authors believe the ability to image collagen and lipids within the breast tissue could serve as an important milestone in breast US-OT imaging with many potential downstream clinical applications. Hence, we would like to present the first-in-human US-OT demonstration of lipid and collagen differentiation in an excised breast tissue from a 38-year-old female.

Immuno-Modulatory Effects of Microparticles Formulated from Degradable Polystyrene Analogue.

Environmental accumulation of non-degradable polystyrene (PS) microparticles from plastic waste poses potential adverse impact on marine life and human health. Herein, microparticles from a degradable PS analogue (dePS) are formulated and their immuno-modulatory characteristics are comprehensively evaluated. Both dePS copolymer and microparticles are chemically degradable under accelerated hydrolytic condition. In vitro studies show that dePS microparticles are non-toxic to three immortalized cell lines. While dePS microparticles do not induce macrophage polarization in vitro, dePS microparticles induce in vivo upregulation of both pro-inflammatory and anti-inflammatory biomarkers in immuno-competent mice, suggesting the coexistence of mixed phenotypes of macrophages in the host immune response to these microparticles. Interestingly, on day 7 following subcutaneous in mice, dePS microparticles induce a lower level of several immuno-modulatory biomarkers (matrix metallo-proteinases (MMPs), tumor necrosis factor (TNF-α), and arginase activity) compared to that of reference poly(lactic-co-glycolic acid) microparticles. Remarkably, compared to PS microparticles, dePS microparticles exhibit similar in vitro and in vivo bioactivity while acquiring additional chemical degradability. Overall, this study gains new insights into the host immune response to dePS microparticles and suggests that this dePS analogue might be explored as an alternative material choice for biomedical and consumer care applications.

A simple mnemonic, B.U.R.N.S., for burns first aid.

INTRODUCTION: Burn injuries remain common in the world, with an average of more than thousands of cases requiring medical attention each year. Singapore sees an average of 220 burns admissions annually. Given the high number of burn cases in Singapore, the authors identified that there is a need for more public awareness on first aid burn treatment. Acute management of burns can improve eventual patient outcome. The authors devised a simple mnemonic that can be used in burns education for first aid treatment, intended to be taught to trained personnel, who will have the first contact with these burn patients. The aim of the study was to assess the viability of implementing this mnemonic, B.U.R.N.S, to facilitate first aid education for burns. MATERIAL AND METHODS: In this study, we presented this mnemonic as a poster to 30 full-time burn care medical professionals. Feedback was then obtained from this group of medical professionals and used to revise the mnemonic. The mnemonic was then subsequently taught to 400 medical professionals, who are predominantly involved in the pre-hospital management of burns. They are then asked to reiterate the mnemonic to test the ease of remembering the mnemonic. Objective feedback was obtained with a 5-point scoring system. RESULTS: The results indicated a significant improvement in burn first aid knowledge after the implementation of the mnemonic, from a score of 3.67-4.77, The content was deemed as appropriate and easy to understand and recall, and participants were able to reiterate the content, and will recommend this mnemonic to be used for burns teaching for first aid. CONCLUSION: The study results suggest that this B.U.R.N.S. mnemonic and visual aid is simple and easy to apply, especially for uniformed personnel, as these individuals may have the first contact with the burns victims, and it is important for them to render the appropriate burns first aid treatment. Overall, burns first aid awareness and education can be improved with the implementation of this mnemonic and poster. Moving forward, we aim to integrate the B.U.R.N.S. into educational programmes in professional institutions involved in responding to burns (medical and nursing schools of Singapore), as well as in schools and public institutions, for educational purpose to raise public awareness. We wish to also be able to do so on an international level when courses are conducted.

Kikuchi-Fujimoto Disease Post COVID-19 Vaccination: Case Report and Review of Literature.

With the rapid development of various coronavirus disease 2019 (COVID-19) vaccines in a bid to counter and contain the COVID-19 pandemic, unusual and uncommon side effects of COVID-19 vaccination have been increasingly reported in the literature. Ipsilateral lymphadenopathy is a fairly common side effect of vaccination of any kind, with its etiology most commonly related to reactive lymphadenopathy. However, Kikuchi-Fujimoto Disease (KFD) or necrotizing histiocytic lymphadenitis is rarely observed post-vaccination, with only one other case of KFD post COVID-19 vaccination reported to date. We report two more cases of KFD post COVID-19 vaccination in the Asian population, highlighting the clinical course and salient clinical, radiological and histologic findings. In addition, we provide a literature review of the existing cases of lymphadenopathy post COVID-19 vaccination with cytologic and/or histologic correlation.

Ectopic Cervical Thyroid Tissue Affected by Fibrosing Hashimoto's Thyroiditis Mimicking Multifocal Metastatic Papillary Thyroid Carcinoma-A Hard Lesson Learnt from an Unusual Case.

We describe a case of ectopic cervical thyroid tissue which was involved by fibrosing Hashimoto's thyroiditis and which mimicked metastatic papillary thyroid carcinoma both on fine needle aspiration cytology and biopsy. The patient underwent total thyroidectomy which revealed fibrosing Hashimoto's thyroiditis, but no carcinoma. The entire thyroidectomy specimen was submitted for histopathological assessment. Even in the resected thyroidectomy specimen, there were cytological changes that were strongly reminiscent of papillary thyroid carcinoma. However, interpreted in the correct clinico-pathological context, these cytological alterations were deemed to be reactive secondary to the fibro-inflammatory process.

Cohort profile: Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO).

The Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) is a preconception, longitudinal cohort study that aims to study the effects of nutrition, lifestyle, and maternal mood prior to and during pregnancy on the epigenome of the offspring and clinically important outcomes including duration of gestation, fetal growth, metabolic and neural phenotypes in the offspring. Between February 2015 and October 2017, the S-PRESTO study recruited 1039 Chinese, Malay or Indian (or any combinations thereof) women aged 18-45 years and who intended to get pregnant and deliver in Singapore, resulting in 1032 unique participants and 373 children born in the cohort. The participants were followed up for 3 visits during the preconception phase and censored at 12 months of follow up if pregnancy was not achieved (N = 557 censored). Women who successfully conceived (N = 475) were characterised at gestational weeks 6-8, 11-13, 18-21, 24-26, 27-28 and 34-36. Follow up of their index offspring (N = 373 singletons) is on-going at birth, 1, 3 and 6 weeks, 3, 6, 12, 18, 24 and 36 months and beyond. Women are also being followed up post-delivery. Data is collected via interviewer-administered questionnaires, metabolic imaging (magnetic resonance imaging), standardized anthropometric measurements and collection of diverse specimens, i.e. blood, urine, buccal smear, stool, skin tapes, epithelial swabs at numerous timepoints. S-PRESTO has extensive repeated data collected which include genetic and epigenetic sampling from preconception which is unique in mother-offspring epidemiological cohorts. This enables prospective assessment of a wide array of potential determinants of future health outcomes in women from preconception to post-delivery and in their offspring across the earliest development from embryonic stages into early childhood. In addition, the S-PRESTO study draws from the three major Asian ethnic groups that represent 50% of the global population, increasing the relevance of its findings to global efforts to address non-communicable diseases.

The Milan system for reporting salivary gland cytology: A retrospective analysis of 1384 cases in a tertiary Southeast Asian institution.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) aims to provide a common language for risk stratification and management. We examine the incidence of MSRSGC categories and the corresponding risk of malignancy (ROM) within a tertiary referral centre in Southeast Asia. METHODS: Salivary gland fine needle aspirations (FNAs) performed within a 10-year period were classified retrospectively according to the MSRSGC. Cytohistologic correlation was performed. The results were compared with the existing literature, including Asian and Western studies. RESULTS: A total of 1384 salivary gland FNAs were evaluated, 421 with corresponding histology. The category distribution was: nondiagnostic, 28.9%; nonneoplastic, 18.0%; atypia of undetermined significance (AUS), 9.8%; benign neoplasm, 32.9%; salivary gland neoplasm of uncertain malignant potential (SUMP), 5.7%; suspicious for malignancy, 1.6%; and malignant, 3.2%. The ROMs were: nondiagnostic, 10.0%; nonneoplastic, 17.5%; AUS, 29.5%; benign neoplasm, 0.5%; SUMP, 17.1%; suspicious for malignancy, 83.3%; and malignant, 100.0%. Our relatively high nondiagnostic rate likely reflects preanalytical factors, whereas our low malignancy rate may be related to population and health care accessibility. Our nonneoplastic ROM was 17.5% compared with 5% to 10% in the literature, likely due to the relatively small number of excised cases; the ROM for SUMP was 17.1% versus 21% to 44% in the literature, possibly reflecting a significant proportion of benign basaloid neoplasms on histology. Interestingly, all false-negative cases in the nonneoplastic category were lymphoid-rich lesions. CONCLUSION: This is one of the largest single-institution studies in the existing literature documenting both the incidence and ROMs of MSRSGC categories. We also highlight specific challenges surrounding lymphoid-rich lesions.

Maternal sensitivity during infancy and the regulation of startle in preschoolers.

Caregiving insensitivity and fear dysregulation predict anxiety symptoms in children. It is unclear, however, whether sensitive parental care during infancy predicts fear regulation later in childhood. To address this question, we asked whether observed maternal sensitivity, measured at 6 months, predicts 42-month-old children's laboratory-induced fear responses (n=213) during a fear-eliciting episode. We predicted that higher levels of maternal sensitivity would be associated with greater fear regulation. We operationalized fear regulation as decreases in fear over repeated trials of a novel, potentially frightening, stimulus. Two aspects of fear responses were considered: expressed fear and startle. Expressed fear scores did not decrease over time but children exhibited less startle behavior in the second half of the task. Maternal sensitivity predicted this startle attenuation across trials. These findings highlight the contribution of maternal sensitivity during infancy to the development of fear regulation in early childhood, further suggesting its influence on offspring anxiety problems.

A Rare Case of Persistent Unilateral Gestational Gigantomastia.

A 34-year-old para 2 + 0 Indonesian woman presented with persistent right-sided gestational gigantomastia some 24 months following delivery. This was severely debilitating her activities of daily living, including caring for her children. On examination, she was found to have extreme hypertrophy of her right breast, which was nodular throughout on palpation. Biochemical investigations were unremarkable and revealed no obvious etiology. Magnetic resonance imaging identified grossly enlarged right breast tissue with prominent vessels. Given the minimal involution of her breast over the 24 months postpartum, she elected for a breast reduction with free nipple grafting following appropriate counseling. This was performed through excision of breast parenchyma preserving superior-medial tissue, followed by a free nipple graft.

Maternal care in infancy and the course of limbic development.

Maternal care may predict limbic development, though relations may vary by age and type of assessment. Here, we examined maternal behavior during early infancy (i.e., six months postpartum) in relation to offspring hippocampal and amygdala volume and microstructure development between 4.5 (n = 99) and 6 (n = 111) years. In interaction with offspring sex, maternal sensitivity predicted left amygdala volume at 6.0 years (ß=-0.214, p = 0.032, df = 89) and independently predicted predominately left lateralized aspects of amygdala and hippocampal microstructure at both time points (hippocampus: left FA at 4.5 years [ß=-0.241, p = 0.043, df = 68], and, in interaction with sex, left [(ß = 0.349, p = 0.022, df = 86) and right FA at 6 years (ß = 0.357, p = 0.016, df = 86] and left MD growth [ß = -0.517, p = 0.021, df = 37]; amygdala: left MD at 4.5 years [ß = -0.319, p = 0.007, df = 69] and, in interaction with offspring sex, left MD growth [ß = -0.546, p = 0.019, df = 37]). Results suggest exposure to non-extreme, early insensitive care impacts neuroanatomy important to learning and stress regulation, perhaps by accelerating development. This underscores the need to promote sensitive caregiving during early infancy within community samples.

An initial investigation of neonatal neuroanatomy, caregiving, and levels of disorganized behavior.

Attachment disorganization is a risk factor for difficulties in attention, social relationships, and mental health. Conceptually, attachment disorganization may indicate a breakdown in fear regulation resulting from repeated exposure to frightening maternal care. In addition, past research has examined the influence of stress-inducing contextual factors and/or child factors upon the development of disorganization. However, no past work has assessed whether infant neuroanatomy, important to stress regulation, moderates the association between maternal care and levels of disorganized behavior. Here, utilizing data from a subsample of 82 dyads taking part in the "Growing Up in Singapore towards Healthy Outcomes" (GUSTO) cohort, we assessed the prediction from maternal sensitive caregiving at 6 mo and levels of attachment disorganization at 1.5 y, as moderated by hippocampal and amygdala volume determined within the first 2 weeks of life. Results indicate a significant interaction between neonatal left hippocampal volume and maternal sensitivity upon levels of disorganized behavior. Although these results require substantiation in further research, if replicated, they may enable new strategies for the identification of processes important to child mental health and points for intervention. This is because neonatal neuroanatomy, as opposed to genetic variation and sociodemographic risk, may be more directly linked to stress responses within individuals.

The development of spatial and memory circuits in the rat.

We provide a concise review of recent studies related to the development of neural circuits supporting spatial navigation and memory in the rat. We chart the relative timeline of the emergence of the four main classes of spatially tuned neurons within the hippocampus and related limbic areas: head direction cells emerge earliest (postnatal day 12, P12), before the eyes of the rats are even open, followed by place cells and boundary responsive cells; grid cells emerge last, around the age of weaning (P21). The rate of maturation is unique to each type of neuron, with the head direction and grid cells showing rapid developmental spurts, in contrast to place cells, which show a more gradual trend of maturation. Interestingly, the emergence of allocentric spatial abilities occurs only after the full complement of spatial neurons becomes functional at P20-21, whereas associative processing in the place cell network is evident from as early as P16. We also present evidence supporting the view that the sensory inputs, which are particularly salient to adult spatial networks, may not be essential for the immature spatial system. Crucially, visual information, although more salient than other sensory modalities for anchoring the adult head direction system, does not appear to be essential for setting up the immature head direction network. We conclude by highlighting an urgent need for new theoretical models that can account for the sequential emergence of spatial cells, as well as the lack of primacy of vision in the early organization of the head direction network. WIREs Cogn Sci 2017, 8:e1424. doi: 10.1002/wcs.1424 For further resources related to this article, please visit the WIREs website.

The development of the head direction system before eye opening in the rat.

Head direction (HD) cells are neurons found in the hippocampal formation and connected areas that fire as a function of an animal's directional orientation relative to its environment. They integrate self-motion and environmental sensory information to update directional heading. Visual landmarks, in particular, exert strong control over the preferred direction of HD cell firing. The HD signal has previously been shown to appear adult-like as early as postnatal day 16 (P16) in the rat pup, just after eye opening and coinciding with the first spontaneous exploration of its environment. In order to determine whether the HD circuit can begin its organization prior to the onset of patterned vision, we recorded from the anterodorsal thalamic nucleus (ADN) and its postsynaptic target in the hippocampal formation, the dorsal pre-subiculum (PrSd), before and after eye opening in pre-weanling rats. We find that HD cells can be recorded at the earliest age sampled (P12), several days before eye opening. However, this early HD signal displays low directional information content and lacks stability both within and across trials. Following eye opening, the HD system matures rapidly, as more cells exhibit directional firing, and the quality and reliability of the directional signal improves dramatically. Cue-rotation experiments show that a prominent visual landmark is able to control HD responses within 24 hr of eye opening. Together, the results suggest that the directional network can be organized independently of visual spatial information while demonstrating the importance of patterned vision for accurate and reliable orientation in space.

Kv7/KCNQ channels control action potential phasing of pyramidal neurons during hippocampal gamma oscillations in vitro.

While the synaptic mechanisms involved in the generation of in vitro network oscillations have been widely studied, little is known about the importance of voltage-gated currents during such activity. Here we study the role of the M-current (I(M)) in the modulation of network oscillations in the gamma-frequency range (20-80 Hz). Kv7/KCNQ subunits, the molecular correlates of I(M), are abundantly expressed in CA1 and CA3 pyramidal neurons, and I(M) is an important modulator of pyramidal neuron firing. Using hippocampal slices, we recorded field activity and pyramidal neuron action potential timing during kainate-induced gamma oscillations. Application of the specific I(M) blocker XE991 causes a significant reduction of gamma oscillation amplitude with no significant change in oscillation frequency. Concomitant CA3 pyramidal neuron recordings show a significant increase in action potential frequency during ongoing gamma oscillations after the application of XE991. This increase is associated with a significant loss of periodicity of pyramidal neuron action potentials relative to the phase of the gamma oscillations. Using dynamic clamp, we show that I(M) acts to improve the periodicity of action potential timing and to decrease action potential frequency. We further validate these results in a compartmental model of a pyramidal neuron. Our work suggests that I(M) modulates gamma oscillations by regulating the phasing of action potential firing in pyramidal neurons.

[Study on the ultraviolet spectra of diacetone acrylamide].

Diacetone acrylamide (DAAM) is an important monomer which can be copolymerized with other monomers, so the copolymers with different properties can be obtained. In the present paper, the ultraviolet spectra of diacetone acrylamide solutions in four different solvents (water, acetonitrile, methanol, cyclohexane) were studied, and it was found that there were two strong absorption peaks around 200 nm and 226 nm, respectively. The absorption peak around 200 nm was sensitive to the polarity of the solvent. The absorption shifted to the lower wavelength as the polarity of the solvent was increased, especially in water and acetonitrile. And the adsorption shifted to longer wavelength with the increase in the concentration. However, the other absorption peak at 226 nm remained basically stable when the concentration or the polarity of the solvent was changed. Obviously the absorption at 226 nm is reasonably considered as a characteristic peak of DAAM in the ultraviolet quantitative analysis. And the other absorption peak at 200 nm which is sensitive to the solvent and concentration can be taken to study the interactions between DAAM and solvent molecules. Also, the strength of the adsorption was affected by the polarity of the solvent.