A Case of Infective Endocarditis in a Middle-Aged Patient With Trisomy 21 and an Incidentally Discovered Patent Foramen Ovale (PFO).

Trisomy 21 often leads to cardiac complications, usually associated with congenital heart disease, such as atrial septal defects, ventricular septal defects, and patent ductus arteriosus. This case describes an unexpected instance of infective endocarditis (IE) in a middle-aged patient with an incidentally discovered patent foramen ovale (PFO). The common risk factors for IE include previous valve surgery, artificial heart valves, pacemakers, prior IE, congenital defects like bicuspid aortic valve, IV drug use, and the congenital defects mentioned earlier.

Right Upper Quadrant Pain: A Rare Presentation of Diverticulitis.

Acute diverticulitis is a prevalent medical condition with increasing incidence rates. While the sigmoid colon is the most commonly affected part of the large intestine, there have been occurrences of right-sided diverticulitis although uncommon. We present a case report highlighting the atypical presentation of diverticulitis in a 27-year-old female patient. The patient experienced right upper and epigastric pain and was ultimately diagnosed with right-sided diverticulitis, supported by her CT imaging findings. This uncommon presentation underscores the importance of considering diverse clinical manifestations when diagnosing and managing diverticulitis.

KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma.

Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers.

Neopetrotaurines A-C, Isoquinoline Alkaloids with an Unprecedented Taurine Bridge from the Sponge Neopetrosia sp.

Neopetrotaurines A-C (1-3), unusual alkaloids possessing two isoquinoline-derived moieties that are linked via a unique taurine bridge, were isolated from a Neopetrosia sp. marine sponge. These new compounds have proton-deficient structural scaffolds that are difficult to unambiguously assign using only conventional 2- and 3-bond 1H-13C and 1H-15N heteronuclear correlation data. Thus, the application of LR-HSQMBC and HMBC NMR experiments optimized to detect 4- and 5-bond long-range 1H-13C heteronuclear correlations facilitated the structure elucidation of these unusual taurine-bridged marine metabolites. Neopetrotaurines A-C (1-3) showed significant inhibition of transcription driven by the oncogenic fusion protein PAX3-FOXO1, which is associated with alveolar rhabdomyosarcoma, and cytotoxic activity against PAX3-FOXO1-positive cell lines.

Is Losing Weight Worth Losing Your Kidney: Keto Diet Resulting in Renal Failure.

Keto diet is defined as a high-fat, adequate-protein, and low-carbohydrate nutrition which forces the body to burn fats and use an alternative metabolic fuel resource by stimulating endogenous ketone production. The standard range of ketones in ketosis is up to 3.00mmol/L, and anything beyond this level can result in serious medical conditions. This diet's most common and easily reversible consequences are constipation, low-grade acidosis, hypoglycemia, kidney stones, and increased lipid in the blood. We present a case of a 36-year-old female who presented with pre-renal azotemia after starting a keto diet regimen.

Dysphagia Lusoria Causing Aspiration Pneumonitis in a Patient With Recurrent Pancreatitis.

Dysphagia lusoria (DL) occurs due to an aberrant right subclavian artery (ARSA) compressing the esophagus resulting in dysphagia, odynophagia, and/or reflux symptoms. It is diagnosed by barium esophagram followed by a CT scan or MRI. In this case report, there is a 44-year-old male with a chronic history of reflux and a cough that presents after a meal. The case was complicated due to the history of the patient's alcoholism with recurrent pancreatitis. A CT scan was obtained during his admission, which showed pleural effusion, atelectasis, aspiration pneumonia, and an incidental aberrant RCA. Although DL is a rare pathology, 60%-80% of patients remain asymptomatic, and patients with symptoms can be managed conservatively or surgically, depending on their severity.

Nocardia in an Immunocompetent Host Masquerading As Lung Cancer: A Case Report.

Nocardiosis is generally regarded as an opportunistic infection that can present as a cutaneous, pulmonary, or disseminated disease based on host immunity status. Pulmonary nocardiosis is typically seen in immunocompromised patients; however, it can rarely be present in immunocompetent patients. We present a rare case of an immunocompetent patient who was thought to have a lung malignancy but was found to have pulmonary nocardiosis upon further investigation.

The Need to Anticoagulate Patients With Splenic Vein Thrombosis.

Splenic vein thrombosis (SVT) is a well-recognized complication of acute and chronic pancreatitis. It is associated with complications of significant gastrointestinal bleeding and high morbidity if the thrombus propagates. There is a need to consider several factors in choosing whether to anticoagulate the patient. We report a case of SVT in a patient with a previous history of pancreatitis who presented with abdominal pain, nausea, and vomiting to the hospital. At the hospital, a CT scan revealed SVT. This case highlights the importance of undergoing further studies regarding anticoagulation for treating SVT in patients at risk for gastrointestinal bleeding.

What Works for One May Not Work for Another: A New Warning for Modafinil.

Narcolepsy is a clinical syndrome of hypothalamic disorder characterized by several sleep-wake disorders. The most common features include daytime sleepiness associated with hallucinations (hypnagogic and hypnopompic hallucinations) at the transition time of sleep-wake time, cataplexy or sudden loss of muscle tone, and sleep paralysis. We present a case of a patient affected with both narcolepsy and postural orthostatic tachycardia syndrome (POTS). POTS is a rare disorder characterized by orthostatic intolerance and abnormal autonomic response while sustaining an upright posture. In this case report, we highlight the impact of POTS on the choice of pharmacotherapy for narcolepsy.

Epstein-Barr Virus-Positive Not Otherwise Specified (EBV+ NOS) Lymphoma Presentation of Primary Bone Tumor Underlying a Pathological Fracture.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma (NHL) and accounts for approximately 25% of all NHLs in developed countries. The patients usually present with constitutional symptoms and rapidly enlarging lymphadenopathy and symptomatic mass typically located in the neck or abdomen, along with an aggressive disease course. Most of the patients present with advanced disease with 60% presenting with stage 3 or 4, and those who present with extranodal involvement are usually seen at an earlier stage. Different conditions are associated with non-Hodgkin's lymphoma ranging from hereditary immunodeficiency disorders, autoimmune disorders, infections such as HIV, Epstein-Barr virus (EBV), hepatitis C virus (HCV), Helicobacter pylori, and drugs such as immunosuppressants and chemotherapeutic agents. Epstein-Barr virus (EBV) is the main etiology of DLBCLs with an identified cause and it accounts for 10% of all DLBCLs.  We report a case of a 51-year-old woman who came with a non-traumatic left femur fracture and was subsequently found to have EBV-positive DLBCL. Lymphoma commonly presents as a lymph node swelling and it's uncommon to present as primary bone disease.

Dentithecamides A-H, Diacylated Zoanthoxanthin Derivatives with PAX3-FOXO1 Inhibitory Activity from the Hydroid Dentitheca habereri.

Chemical investigation of the marine hydroid Dentitheca habereri led to the identification of eight new diacylated zoanthoxanthin alkaloids, named dentithecamides A-H (1-8), along with three previously reported analogues, zoamides B-D (9-11). The structures of compounds 1-11 were elucidated by spectroscopic and spectrometric analyses, including IR, HRESIMS, and NMR experiments, and by comparison with literature data. Compounds 1-11 are the first zoanthoxanthin alkaloids to be reported from a hydroid. Dentithecamides A (1) and B (2) along with zoamides B-D (9-11), which all share a conformationally mobile cycloheptadiene core, inhibited PAX3-FOXO1 regulated transcriptional activity and thus provided a structural framework for the potential development of more potent PAX3-FOXO1 inhibitors.

Correction: What Works for One May Not Work for Another: A New Warning for Modafinil.

[This corrects the article DOI: 10.7759/cureus.27287.].

Insight into mithramycin disruption of ETS transcription leads to improved understanding of more selective analogs.

Fusion products with the ETS family of transcription factors play critical roles in the etiology of several cancers. In this issue of Structure, Hou et al. (2020) provide insight into allosteric mechanisms by which mithramycin and its analogs perturb protein-DNA interactions in higher-order complexes at a DNA enhancer site.

Neopetrothiazide: An Intriguing Pentacyclic Thiazide Alkaloid from the Sponge Neopetrosia sp.

Neopetrothiazide (1), a pentacyclic isoquinoline quinone, was isolated from a Neopetrosia sp. sponge. The structure elucidation was facilitated by utilizing long-range heteronuclear single quantum multiple bond correlation (LR-HSQMBC) and heteronuclear multiple bond correlation (HMBC) nuclear magnetic resonance (NMR) pulse sequences optimized to detect four- and five-bond 1H-13C heteronuclear correlations. These NMR experiments can help assign proton-deficient structural motifs like neopetrothiazide (1), which has 14 contiguous nonprotonated centers (C, N, and S). Neopetrothiazide (1), with an unprecedented thiazide-fused structural scaffold, is the first natural product containing a thiazide moiety.

Denigrins and Dactylpyrroles, Arylpyrrole Alkaloids from a Dactylia sp. Marine Sponge.

Seven new arylpyrrole alkaloids (1-7), along with four known compounds, were isolated from an extract of a Dactylia sp. nov. marine sponge, and their structures were elucidated by interpretation of NMR and MS spectroscopic data. Denigrins D-G (1-4) have highly substituted pyrrole or pyrrolone rings in their core structures, while dactylpyrroles A-C (5-7) have tricyclic phenanthrene cores. Due to the proton-deficient nature of these scaffolds, key heteronuclear correlations from 1H-15N HMBC and LR-HSQMBC NMR experiments were used in the structure assignment of denigrin D (1). Dictyodendrin F (8), a previously described co-metabolite, inhibited transcription driven by the oncogenic PAX3-FOXO1 fusion gene with an IC50 value of 13 µM.

Chemical genomics reveals histone deacetylases are required for core regulatory transcription.

Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry are of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs to induce the expression of other CR TFs, providing a model system for studying cancer cell addiction to CR transcription. Using chemical genetics, the systematic screening of chemical matter for a biological outcome, here we report on a screen for epigenetic chemical probes able to distinguish between SE-driven transcription and constitutive transcription. We find that chemical probes along the acetylation-axis, and not the methylation-axis, selectively disrupt CR transcription. Additionally, we find that histone deacetylases (HDACs) are essential for CR TF transcription. We further dissect the contribution of HDAC isoforms using selective inhibitors, including the newly developed selective HDAC3 inhibitor LW3. We show HDAC1/2/3 are the co-essential isoforms that when co-inhibited halt CR transcription, making CR TF sites hyper-accessible and disrupting chromatin looping.

Madecassic Acid Derivatives as Potential Anticancer Agents: Synthesis and Cytotoxic Evaluation.

A series of novel madecassic acid (1) derivatives was synthesized, and their cytotoxicity was evaluated against the NCI-60 panel of cancer cell lines. Several analogues exhibited broad-spectrum cytotoxic activities over all nine tumor types represented in the panel, with more potent antiproliferative activities observed against selected cancer cell lines, including multidrug-resistant phenotypes. Among them, compound 29 showed GI50 (50% growth inhibition) values ranging from 0.3 to 0.9 µM against 26 different tumor cell lines and selectivity for one colon (COLO 205) and two melanoma (SK-MEL-5 and UACC-257) cell lines at the TGI (total growth inhibition) level. The mode of action of 29 was predicted by CellMiner bioinformatic analysis and confirmed by biochemical and cell-based experiments to involve inhibition of the DNA replication process, particularly the initiation of replication, and disruption of mitochondrial membrane potential. The present findings suggest this novel madecassic acid derivative may have potential as an anticancer therapeutic lead for both solid and hematological tumors.

Elucidation of Spirodactylone, a Polycyclic Alkaloid from the Sponge Dactylia sp., and Nonenzymatic Generation from the Co-metabolite Denigrin B.

Spirodactylone (1), a hexacyclic indolizidone alkaloid possessing a novel spiro ring system, was isolated from the marine sponge Dactylia sp. The structure was elucidated by extensive spectroscopic methods including application of the LR-HSQMBC NMR pulse sequence. Oxidative cyclization of denigrin B (2), an aryl-substituted 2-oxo-pyrroline derivative that was also isolated from the sponge extract, provided material identical to spirodactylone (1). This confirmed the assigned structure and provides insight into the probable biogenesis of 1.

Blood Pressure and Arterial Load After Transcatheter Aortic Valve Replacement for Aortic Stenosis.

BACKGROUND: After aortic valve replacement, left ventricular afterload is often characterized by the residual valve obstruction. Our objective was to determine whether higher systemic arterial afterload-as reflected in blood pressure, pulsatile and resistive load-is associated with adverse clinical outcomes after transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: Total, pulsatile, and resistive arterial load were measured in 2141 patients with severe aortic stenosis treated with TAVR in the PARTNER I trial (Placement of Aortic Transcatheter Valve) who had systolic blood pressure (SBP) and an echocardiogram obtained 30 days after TAVR. The primary end point was 30-day to 1-year all-cause mortality. Lower SBP at 30 days after TAVR was associated with higher mortality (20.0% for SBP 100-129 mm Hg versus 12.0% for SBP 130-170 mm Hg; P<0.001). This association remained significant after adjustment, was consistent across subgroups, and confirmed in sensitivity analyses. In adjusted models that included SBP, higher total and pulsatile arterial load were associated with increased mortality (P<0.001 for all), but resistive load was not. Patients with low 30-day SBP and high pulsatile load had a 3-fold higher mortality than those with high 30-day SBP and low pulsatile load (26.1% versus 8.1%; hazard ratio, 3.62; 95% confidence interval, 2.36-5.55). CONCLUSIONS: Even after relief of valve obstruction in patients with aortic stenosis, there is an independent association between post-TAVR blood pressure, systemic arterial load, and mortality. Blood pressure goals in patients with a history of aortic stenosis may need to be redefined. Increased pulsatile arterial load, rather than blood pressure, may be a target for adjunctive medical therapy to improve outcomes after TAVR. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894.

Impact of Preoperative Chronic Kidney Disease in 2,531 High-Risk and Inoperable Patients Undergoing Transcatheter Aortic Valve Replacement in the PARTNER Trial.

BACKGROUND: Although preoperative renal dysfunction (RD) is associated with increased mortality and morbidity after surgical aortic valve replacement, its impact on clinical outcomes after transcatheter aortic valve replacement (TAVR) is less defined. METHODS: TAVR patients in the PARTNER (Placement of Aortic Transcatheter Valves) trial with a calculable glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease equation were included. Patients were divided into three groups: GFR >60 mL/min (none/mild RD), GFR 31 to 60 mL/min (moderate RD), and GFR ≤30 mL/min (severe RD). Operative characteristics and clinical outcomes were analyzed. Cox regression models were used to determine multivariable predictors of 1-year all-cause mortality. RESULTS: A total of 2,531 inoperable or high surgical risk patients from the PARTNER trial and continued access registries had a calculable GFR level: 767 (30%) had normal renal function or mild RD, 1,473 (58%) had moderate RD, and 291 (12%) presented with severe RD. The mean Society of Thoracic Surgeons Predicted Risk of Mortality for the cohort was 11.5%, and it was highest in those with severe RD (13.8%). Patients with severe RD were more often women with a higher prevalence of diabetes. Patients with severe RD had the highest incidence of 30-day and 1-year all-cause mortality and rehospitalization. The 30-day rate of death from any cause was 10.7% in the severe RD group versus 6.0% in the moderate and mild RD groups (p = 0.01). The 1-year rate of death from any cause was 34.4% in the severe RD group versus 21.5% in the moderate RD and 20.8% in the none/mild RD groups (adjusted hazard ratio [HR] 2.24, p < 0.0001 for severe versus none/mild; adjusted HR 1.14, p = 0.24 for severe versus moderate). Other significant predictors of 1-year all-cause mortality included lower body mass index, frailty, the transapical approach, a lower ejection fraction, oxygen-dependent chronic obstructive pulmonary disease, liver disease, and male sex. CONCLUSIONS: Preoperative severe RD is a significant predictor for 1-year mortality in TAVR patients. Careful risk stratification by the heart team is required in patients with severe preprocedural RD.