Gastric outlet obstruction in an 11-year-old girl: A case report.

Pyloric stenosis commonly affects infants and rarely causes gastric outlet obstruction in adolescents and older children. We present the case of an 11-year-old girl with a 2-month history of recurrent postprandial vomiting and weight loss. On physical examination, the patient presented with abdominal distension. Upper gastrointestinal endoscopy revealed a very small pyloric orifice through which the endoscope could not be advanced. Abdominal ultrasonography and a computed tomography confirmed pylorus thickening. She underwent Heineke-Mikulicz pyloroplasty with symptom resolution.

Functional Diversity of Memory CD8 T Cells is Spatiotemporally Imprinted.

Tissue-resident memory CD8 T cells (TRM) kill infected cells and recruit additional immune cells to limit pathogen invasion at barrier sites. Small intestinal (SI) TRM cells consist of distinct subpopulations with higher expression of effector molecules or greater memory potential. We hypothesized that occupancy of diverse anatomical niches imprints these distinct TRM transcriptional programs. We leveraged human samples and a murine model of acute systemic viral infection to profile the location and transcriptome of pathogen-specific TRM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. TRM populations were spatially segregated: with more effector- and memory-like TRM preferentially localized at the villus tip or crypt, respectively. Modeling ligand-receptor activity revealed patterns of key cellular interactions and cytokine signaling pathways that initiate and maintain TRM differentiation and functional diversity, including different TGFß sources. Alterations in the cellular networks induced by loss of TGFßRII expression revealed a model consistent with TGFß promoting progressive TRM maturation towards the villus tip. Ultimately, we have developed a framework for the study of immune cell interactions with the spectrum of tissue cell types, revealing that T cell location and functional state are fundamentally intertwined.

New MoS2/Tegafur-Containing Pharmaceutical Formulations for Selective LED-Based Skin Cancer Photo-Chemotherapy.

Non-melanoma skin cancer (NMSC) is one of the most common types of cancer worldwide. Despite the low mortality rate, rising incidence and recurrence rates are a burden on healthcare systems. Standard treatments such as chemotherapy, radiotherapy, and surgery are either invasive or toxic to healthy tissues; therefore, new, alternative, selective treatments are needed. In this work, a combined photothermal and chemotherapeutic approach is proposed. MoS2 was used as photothermal agent. It was prepared by a liquid-phase exfoliation and intercalation method using polyvinylpyrrolidone (PVP), followed by recirculation through a custom-built high-power ultrasonication probe. After 6 h of ultrasonication treatment, the average particle size was 165 ± 170 nm. Near-infrared (NIR) irradiation assays (810 nm, 0.1 W/cm2, 30 min, 180 J/cm2) confirmed that MoS2 nanosheets can efficiently convert NIR light into heat and reach 52 °C. The therapeutic doses of MoS2 (125 µg/mL) and Tegafur (50 µg/mL) were optimized and both were simultaneously incorporated into a Carbopol hydrogel. The cells were brought into contact with the hydrogel and irradiated with a custom-built NIR LED system. In HFF-1 cells (normal human fibroblasts), the metabolic activity was 78% (above the 70% toxicity limit-ISO 10993-5:2009(E)), while in A-431 skin cancer cells, it was 28%. In addition, the MoS2 + Tegafur hydrogels led to a 1.9-fold decrease in A-431 cancer cell metabolic activity, 72 h after irradiation, in comparison to MoS2 hydrogels, indicating a combined effect of photothermal and chemotherapy.

txtools: an R package facilitating analysis of RNA modifications, structures, and interactions.

We present txtools, an R package that enables the processing, analysis, and visualization of RNA-seq data at the nucleotide-level resolution, seamlessly integrating alignments to the genome with transcriptomic representation. txtools' main inputs are BAM files and a transcriptome annotation, and the main output is a table, capturing mismatches, deletions, and the number of reads beginning and ending at each nucleotide in the transcriptomic space. txtools further facilitates downstream visualization and analyses. We showcase, using examples from the epitranscriptomic field, how a few calls to txtools functions can yield insightful and ready-to-publish results. txtools is of broad utility also in the context of structural mapping and RNA:protein interaction mapping. By providing a simple and intuitive framework, we believe that txtools will be a useful and convenient tool and pave the path for future discovery. txtools is available for installation from its GitHub repository at https://github.com/AngelCampos/txtools.

Visual-functional impact of people affected by severe ocular trauma during social protests in Chile in 2019.

PURPOSE: To determine the impact on the functionality associated with visual loss (VFIP) in people with severe ocular trauma (SOT) caused by kinetic impact projectiles used in police crowd control through a prioritization tool in people admitted to a rehabilitation program in Santiago de Chile from December 02, 2019, to November 13, 2020. METHODS: A cross-sectional descriptive study of SOT victims (N = 85), average age 31.4 ± 11.9. The data were recorded through a new 9-item screening instrument for assessment and prioritization of rehabilitation created for this emergency scenario. RESULTS: The impact of the use of kinetic weapons resulted in monocular blindness in the majority of those affected (n = 68; 80.0%). The highest VFIP observed was among young men from lower social strata. There were extreme difficulties in the performance of productive tasks (occupational and/or educational) (n = 42; 49.4%) and the pursuit of hobbies and pastimes (n = 23; 27.1%), as well as a high difficulty in adapting to changes in brightness (n = 29; 34.1%) and handling objects accurately (n = 22; 25.9%). CONCLUSION: The use of kinetic weapons for crowd control resulted in high and extreme VFIP and, in most cases, monocular blindness, causing major difficulties in work, study, and development of hobbies and pastimes in the affected population, highlighting the urgent need for effective rehabilitative care, which requires special attention in order to generate an adequate rehabilitation program. The use of kinetic weapons for crowd control contravenes international goals, policies, and plans set by the WHO and the International Agency for the Prevention of Blindness on strategies to prevent avoidable blindness worldwide until 2020. It is essential to ban the use of these weapons in Chile and worldwide, as well as to revise police protocols for crowd control.

Functional impact of multi-omic interactions in lung cancer.

Lung tumors are a leading cause of cancer-related death worldwide. Lung cancers are highly heterogeneous on their phenotypes, both at the cellular and molecular levels. Efforts to better understand the biological origins and outcomes of lung cancer in terms of this enormous variability often require of high-throughput experimental techniques paired with advanced data analytics. Anticipated advancements in multi-omic methodologies hold potential to reveal a broader molecular perspective of these tumors. This study introduces a theoretical and computational framework for generating network models depicting regulatory constraints on biological functions in a semi-automated way. The approach successfully identifies enriched functions in analyzed omics data, focusing on Adenocarcinoma (LUAD) and Squamous cell carcinoma (LUSC, a type of NSCLC) in the lung. Valuable information about novel regulatory characteristics, supported by robust biological reasoning, is illustrated, for instance by considering the role of genes, miRNAs and CpG sites associated with NSCLC, both novel and previously reported. Utilizing multi-omic regulatory networks, we constructed robust models elucidating omics data interconnectedness, enabling systematic generation of mechanistic hypotheses. These findings offer insights into complex regulatory mechanisms underlying these cancer types, paving the way for further exploring their molecular complexity.

Dissecting the sequence and structural determinants guiding m6A deposition and evolution via inter- and intra-species hybrids.

BACKGROUND: N6-methyladenosine (m6A) is the most abundant mRNA modification, and controls mRNA stability. m6A distribution varies considerably between and within species. Yet, it is unclear to what extent this variability is driven by changes in genetic sequences ('cis') or cellular environments ('trans') and via which mechanisms. RESULTS: Here we dissect the determinants governing RNA methylation via interspecies and intraspecies hybrids in yeast and mammalian systems, coupled with massively parallel reporter assays and m6A-QTL reanalysis. We find that m6A evolution and variability is driven primarily in 'cis', via two mechanisms: (1) variations altering m6A consensus motifs, and (2) variation impacting mRNA secondary structure. We establish that mutations impacting RNA structure - even when distant from an m6A consensus motif - causally dictate methylation propensity. Finally, we demonstrate that allele-specific differences in m6A levels lead to allele-specific changes in gene expression. CONCLUSIONS: Our findings define the determinants governing m6A evolution and diversity and characterize the consequences thereof on gene expression regulation.

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.

The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.

Canine follicular cell and medullary thyroid carcinomas: Immunohistochemical characterization.

Research on modulation of iodine uptake by thyroid cells could help improve radioiodine treatment of dogs with thyroid tumors. The aim of this study was to characterize the immunohistochemical expression of thyroid transcription factor-1 (TTF-1), thyroglobulin, thyrotropin receptor (TSHR), sodium iodide symporter (NIS), pendrin, thyroid peroxidase (TPO), vimentin, and Ki-67 in follicular cell thyroid carcinomas (FTCs) and medullary thyroid carcinomas (MTCs), and to compare protein expression between FTC causing hyperthyroidism and FTC of euthyroid dogs. Immunohistochemistry was performed in 25 FTCs (9 follicular, 8 follicular-compact, and 8 compact) and 8 MTCs. FTCs and MTCs were positive for TTF-1, and expression was higher in FTCs of euthyroid dogs compared with FTCs of hyperthyroid dogs (P= .041). Immunolabeling for thyroglobulin was higher in follicular and follicular-compact FTCs compared with compact FTCs (P = .001), while vimentin expression was higher in follicular-compact FTCs compared with follicular FTCs (P = .011). The expression of TSHR, NIS, pendrin, and TPO was not significantly different among the different subtypes of FTCs or between FTCs causing hyperthyroidism and FTCs in euthyroid dogs. TSHR, NIS, pendrin, and TPO were also expressed in MTCs. Ki-67 labeling index was comparable between FTCs and MTCs, and between FTCs causing hyperthyroidism and FTCs in euthyroid dogs. Proteins of iodine transport were also expressed in canine MTCs, which could have implications for diagnosis and treatment. The different expression of thyroglobulin and vimentin between FTC histological subtypes could reflect variations in tumor differentiation.

Metabolic programs of T cell tissue residency empower tumour immunity.

Tissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.

Pre-existing tumor host immunity characterization in resected non-small cell lung cancer.

INTRODUCTION: Neoadjuvant and adjuvant immune checkpoint blockade (ICB) have recently become standard of care in resectable non-small cell lung cancer (NSCLC). Yet, biomarkers that inform patients who benefit from this approach remain largely unknown. Here, we interrogated the tumor immune microenvironment (TIME) in early-stage NSCLC patients that underwent up-front surgery. METHODS: A total of 185 treatment-naïve patients with early-stage NSCLC, that underwent up-front surgical treatment between 2006 and 2018 at Hospital del Mar were included. 124 lung adenocarcinomas (LUADs), and 61 squamous cell carcinoma (LUSCs) were included in a tissue microarray. Immunohistochemistry for CD3, CD4, CD8, CD68, CD80, CD103, FOXP3, PD-1, PD-L1, PD-L2 and HLA class II were evaluated by digital image analysis (QuPath software). TIME was categorized into four groups using PD-L1 expression in tumor cells (<1 % or ≥1 %) and tumor resident memory (CD103+) immune cells (using the median as cut-off). We explored the association between different TIME dimensions and patient's clinicopathological features and outcomes. RESULTS: We found increased levels of T cell markers (CD3+, CD4+, CD8+ cells), functional immune markers (FOXP3+ cells) as well as, higher HLA-II tumor membrane expression in LUADs compared to LUSCs (p < 0.05 for all). In contrast, LUSCs displayed higher percentage of intratumor macrophages (CD68+ cells) as well as, higher PD-L1 and PD-L2 tumor membrane expression (p < 0.05 for all). Unsupervised analysis revealed three different tumor subsets characterized by membrane tumor expression of PD-L1, PD-L2 and HLA-class II. Enrichment of T cells (CD3+, CD8+ cells), regulatory T cells (FOXP3+ cells) and macrophages (CD68+ cells) was observed in the CD103+/PD-L1+ group (p < 0.05 for all). Multivariate analysis showed that infiltration by CD103+ immune cells was associated with improved OS (p = 0.009). CONCLUSIONS: TIME analysis in resected NSCLC highlighted differences by histology, PD-L1 expression and molecular subgroups. Biomarker studies using IHC might aid to individually tailor adjuvant treatment in early-stage NSCLC.

Does PLEX® Elite 9000 OCT Identify and Characterize Most Posterior Pole Lesions in Highly Myopic Patients?

High myopia (HM) is defined as an axial length (AL) ≥ 26 mm that may result in various pathologies that constitute pathologic myopia (PM). The PLEX® Elite 9000 (Carl Zeiss AC, Jena, Germany) is a new swept-source optical coherence tomography (SS-OCT) underdevelopment that allows wider, deeper and more detailed posterior-segment visualization; it can acquire ultra-wide OCT angiography (OCTA) or new ultra-wide high-density scans in one image. We assessed the technology's ability to identify/characterize/quantify staphylomas and posterior pole lesions or image biomarkers in highly myopic Spanish patients and estimate the technology's potential to detect macular pathology. The instrument acquired 6 × 6 OCTA, 12 × 12 or 6 × 6 OCT cubes, and at least two high-definition spotlight single scans. A hundred consecutive patients (179 eyes; age, 51.4 ± 16.8 years; AL, 28.8 ± 2.33 mm) were recruited in one center for this prospective observational study. Six eyes were excluded because images were not acquired. The most common alterations were perforating scleral vessels (88.8%), classifiable staphyloma (68.7%), vascular folds (43%), extrafoveal retinoschisis (24%), dome-shaped macula (15.6%), and more uncommonly, scleral dehiscence (4.46%), intrachoroidal cavitation (3.35%), and macular pit (2.2%). The retinal thickness of these patients decreased, and the foveal avascular zone increased in the superficial plexus compared with normal eyes. SS-OCT is a novel potent tool that can detect most main posterior pole complications in PM and may provide us with a better understanding of the associated pathologies; some pathologies were identifiable only with this new kind of equipment, such as perforating scleral vessels, which seem to be the most common finding and not so frequently related to choroidal neovascularization, as previously reported.

Immunometabolism at the crossroads of obesity and cancer-a Keystone Symposia report.

Immunometabolism considers the relationship between metabolism and immunity. Typically, researchers focus on either the metabolic pathways within immune cells that affect their function or the impact of immune cells on systemic metabolism. A more holistic approach that considers both these viewpoints is needed. On September 5-8, 2022, experts in the field of immunometabolism met for the Keystone symposium "Immunometabolism at the Crossroads of Obesity and Cancer" to present recent research across the field of immunometabolism, with the setting of obesity and cancer as an ideal example of the complex interplay between metabolism, immunity, and cancer. Speakers highlighted new insights on the metabolic links between tumor cells and immune cells, with a focus on leveraging unique metabolic vulnerabilities of different cell types in the tumor microenvironment as therapeutic targets and demonstrated the effects of diet, the microbiome, and obesity on immune system function and cancer pathogenesis and therapy. Finally, speakers presented new technologies to interrogate the immune system and uncover novel metabolic pathways important for immunity.

The Use of a Polylactic Membrane in Pediatric Burns Proves to be Successful Even After Late Application.

The Polylactide membrane (PLM) is a biosynthetic dressing that mimics properties of the human epithelium. Herein we describe our experience on the use of PLM in pediatric burns. All pediatric burn patients admitted to the Pediatric Surgery Department between November 2019 and November 2021 and submitted to PLM application were selected. Clinical and demographic data were collected retrospectively. Seventy-seven patients with a median age of 1.8 years were included. The median total body surface area was 6% (2-20%), and burns were mainly mixed-partial thickness. PLM was applied at a median of 5 days post-burn (IQR 3-6), usually under sedation (43/77). After PLM application, the median healing time (HT) was 10 days (IQR 8-14). HT was significantly higher in deep-partial thickness burns vs. mixed superficial-deep (P = .015) and superficial burn areas (P = .006). No correlation was found between HT and the timing of PLM application. The grafting rate due to clinical misevaluation was 2.7%, one infection was found. The PLM is a promising way for treating partial-thickness burns, even when applied later during treatment. Shorter HT, the decreased need for dressing changes, and the potential of sparing of donor sites and pain reduction are its main advantages.

Genomic, spatial and morphometric data for discrimination of four species in the Mediterranean Tamus clade of yams (Dioscorea, Dioscoreaceae).

BACKGROUND AND AIMS: Among the numerous pantropical species of the yam genus, Dioscorea, only a small group occurs in the Mediterranean basin, including two narrow Pyrenean endemics (Borderea clade) and two Mediterranean-wide species (D. communis and D. orientalis, Tamus clade). However, several currently unrecognized species and infraspecific taxa have been described in the Tamus clade due to significant morphological variation associated with D. communis. Our overarching aim was to investigate taxon delimitation in the Tamus clade using an integrative approach combining phylogenomic, spatial and morphological data. METHODS: We analysed 76 herbarium samples using Hyb-Seq genomic capture to sequence 260 low-copy nuclear genes and plastomes, together with morphometric and environmental modelling approaches. KEY RESULTS: Phylogenomic reconstructions confirmed that the two previously accepted species of the Tamus clade, D. communis and D. orientalis, are monophyletic and form sister clades. Three subclades showing distinctive geographic patterns were identified within D. communis. These subclades were also identifiable from morphometric and climatic data, and introgression patterns were inferred between subclades in the eastern part of the distribution of D. communis. CONCLUSIONS: We propose a taxonomy that maintains D. orientalis, endemic to the eastern Mediterranean region, and splits D. communis sensu lato into three species: D. edulis, endemic to Macaronesia (Canary Islands and Madeira); D. cretica, endemic to the eastern Mediterranean region; and D. communis sensu stricto, widespread across western and central Europe. Introgression inferred between D. communis s.s. and D. cretica is likely to be explained by their relatively recent speciation at the end of the Miocene, disjunct isolation in eastern and western Mediterranean glacial refugia and a subsequent westward recolonization of D. communis s.s. Our study shows that the use of integrated genomic, spatial and morphological approaches allows a more robust definition of species boundaries and the identification of species that previous systematic studies failed to uncover.

Organoids of patient-derived medullary thyroid carcinoma: The first milestone towards a new in vitro model in dogs.

Organoid cultures could constitute a valuable in vitro model to explore new treatments for canine (c) medullary thyroid carcinoma (MTC). The study's objectives were to establish and characterize 3D organoid cultures of cMTC using histology and immunohistochemistry (IHC) and to evaluate the effect of antitumor drugs on organoids' viability. Five cMTC tissue samples were used to develop organoid cultures of which one organoid line, named cMTC N°2, could be passaged for an extended period. This cMTC N°2 organoid line was further compared to the primary tumour regarding morphology and IHC expression of thyroid transcription factor-1 (TTF-1), thyroglobulin, calcitonin, synaptophysin, vimentin, Ki-67, cyclooxygenase-2 (COX-2), P-glycoprotein and vascular endothelial growth factor (VEGF). Quality control of the cMTC N°2 organoid line was achieved by a single nucleotide polymorphism (SNP) array of the organoids, primary tumour and healthy blood cells of the same dog. The effect of carboplatin, meloxicam and toceranib phosphate (TOC) on cMTC N°2 organoids' viability was evaluated. The cMTC N°2 organoid line was cultured for 94 days and showed similar histological features with the primary tumour. Immunolabelling for TTF-1, thyroglobulin, calcitonin and VEGF was similar between the primary tumour and cMTC N°2 organoids. Compared to the primary tumour, organoids showed higher immunolabelling for vimentin and Ki-67, and lower immunolabelling for synaptophysin, COX-2 and P-glycoprotein. The SNP genotype was similar for each chromosome between healthy blood cells, primary tumour and cMTC N°2 organoids. Carboplatin, meloxicam and TOC had no effect on cMTC N°2 organoid cell viability within achievable in vivo concentration range. In conclusion, the cMTC N°2 organoid line is a promising first milestone towards an established in vitro organoid model to explore pathophysiology and new treatment modalities in cMTC.

Minimally invasive treatment of pilonidal sinus disease in a paediatric population: comparison of two techniques.

BACKGROUND: Pilonidal disease (PD) is a common and debilitating inflammatory condition with significant impact on quality of life. Minimally invasive techniques (MIT) have shown promising results comparing to traditional excision. Herein we present a comparison of two MIT techniques -sinusectomy (SE) and pit-picking plus laser ablation (PPL). METHODS: All cases of paediatric PD treated by PPL and SE at our center between August 2018 and August 2020 were retrospectively reviewed. RESULTS: One-hundred and six patients were included, with a median age of 16 years (IQR 15-16). PPL was the procedure of choice in 36 patients (34%) and the remaining underwent SE (66%). Median healing time was significantly lower in SE group (20 days), comparing to PPL (30 days) (p = 0.002). Early healing failure occurred more frequently in the PPL group (p = 0.003). Recurrence rate was similar between groups - PPL 17% versus SE 16% (p = 0.89). Overall complication rate was 9% and was significantly higher in PPL (p = 0.03). CONCLUSIONS: MIT techniques are promising solutions in PD treatment. Although similarly easy and fast to perform, SE technique showed better healing profile and lower complication rate but no significant difference on recurrence rates was observed.

Outcome of radioiodine therapy for feline hyperthyroidism: Fixed dose versus individualized dose based on a clinical scoring system.

Background: Hyperthyroidism is the most frequent endocrinopathy in older cats. To date, there is no consensus on how to best calculate the dose of radioiodine to administer to hyperthyroid cats. Aim: The goals of this study were to compare thyroid function, renal function, and survival time between hyperthyroid cats receiving a fixed dose of radioiodine and those receiving an individualized dose calculated using a clinical scoring system. Methods: Medical records of 110 cats treated with radioiodine therapy at the University of Bern between 2010 and 2020 were reviewed. Thyroid function, renal function, and survival of cats treated with a fixed dose of radioiodine (2010-2015; n = 50) were compared to those of cats treated with an individualized dose (2015-2020; n = 60) at different time points after therapy. Results: Treatment with a fixed dose of radioiodine (mean = 168 ± 26 MBq) was associated with 69% of euthyroidism, 19% persistent hyperthyroidism, and 12% hypothyroidism, whereas treatment with an individualized dose (mean = 120 ± 30 MBq) led to 54% euthyroidism, 23% hyperthyroidism, and 23% hypothyroidism (p = 0.73). More than 12 months after treatment, the incidence of azotemia was comparable between cats treated with a fixed dose (37%) and those treated with an individualized dose (31%) (p = 0.77). No factors were found to be predictive of treatment failure (hypothyroidism or hyperthyroidism) after therapy. Median survival time after radioiodine therapy was 44 months. In a multivariate analysis, persistent hyperthyroidism was the only variable independently associated with a shorter survival time (HR = 6.24, p = 0.002). Conclusion: The method of calculating the dose of radioiodine (fixed vs. individualized) to treat feline hyperthyroidism does not appear to be decisive for posttreatment thyroid function, renal function, or survival.

The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62.

Reduced p62 levels are associated with the induction of the cancer-associated fibroblast (CAF) phenotype, which promotes tumorigenesis in vitro and in vivo through inflammation and metabolic reprogramming. However, how p62 is downregulated in the stroma fibroblasts by tumor cells to drive CAF activation is an unresolved central issue in the field. Here we show that tumor-secreted lactate downregulates p62 transcriptionally through a mechanism involving reduction of the NAD+/NADH ratio, which impairs poly(ADP-ribose)-polymerase 1 (PARP-1) activity. PARP-1 inhibition blocks the poly(ADP-ribosyl)ation of the AP-1 transcription factors, c-FOS and c-JUN, which is an obligate step for p62 downregulation. Importantly, restoring p62 levels in CAFs by NAD+ renders CAFs less active. PARP inhibitors, such as olaparib, mimick lactate in the reduction of stromal p62 levels, as well as the subsequent stromal activation both in vitro and in vivo, which suggests that therapies using olaparib would benefit from strategies aimed at inhibiting CAF activity.

Dilated cardiomyopathy in a cat with congenital hyposomatotropism.

Case summary: A 7-month-old domestic shorthair cat was presented for evaluation of stunted growth, recurrent hypoglycaemia during the first months of its life and altered mentation. Complete blood count and biochemistry were unremarkable, except for mildly elevated serum creatinine concentration (despite low muscle mass) and concurrent isosthenuria. Hyposomatotropism was diagnosed based on persistent low circulating insulin-like growth factor 1 concentrations and a lack of response of circulating growth hormone (GH) concentration after the administration of GH-releasing hormone. Other endocrinopathies such as hypothyroidism and hypoadrenocorticism were excluded. MRI of the brain revealed a fluid-filled empty sella tursica, consistent with a pituitary cyst and atrophy/hypoplasia of the pituitary. Echocardiography was unremarkable at the time of diagnosis of hyposomatotropism. Three months later, ovariohysterectomy revealed immature ovaries, raising the suspicion of luteinising and follicle-stimulating hormone deficiency. At 1 year of age, the cat developed congestive heart failure secondarily to dilated cardiomyopathy (DCM) with severely reduced left ventricular systolic function and died a few days later. Pathology showed atrophy of the adenohypophysis, epithelial delineation of the pituitary cysts, mild cardiomegaly, multifocal fibrosis of the left ventricle and a mild, multifocal, chronic epicarditis. Relevance and novel information: GH deficiency is a very rare endocrinopathy in cats. This is the first case to describe the development of DCM with concurrent hyposomatotropism, which has previously been reported in human medicine. Other notable abnormalities that could be related to GH deficiency are juvenile self-limiting hypoglycaemia, behavioural changes and possible nephropathy.