Citations

Abstract Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

We assessed the available evidence regarding adverse effects on surrogate and patient-important health outcomes of third- and fourth-generation combined oral contraceptives among premenopausal women. We performed a systematic review and meta-analysis including randomized controlled trials and observational studies comparing third- and fourth-generation combined oral contraceptives with other generation contraceptives or placebo. Studies that enrolled women aged 15 to 50 years, with at least three cycles of intervention and 6 months of follow-up were included. A total of 33 studies comprising 629,783 women were included. Low-density lipoprotein cholesterol levels were significantly lower in fourth-generation oral contraceptives (mean differences (MD): −0.24 mmol/L; [95% CI −0.39 to −0.08]), while total cholesterol was significantly increased in levonorgestrel users when compared to third-generation oral contraceptives (MD: 0.27 mmol/L; [95% CI 0.04 to 0.50]). A decreased arterial thrombosis incidence was shown in fourth-generation oral contraceptive users, as compared to levonorgestrel (incidence rate ratio (IRR): 0.41; [95% CI 0.19 to 0.86]). No difference was found in the occurrence of deep venous thrombosis between fourth-generation oral contraceptives and levonorgestrel users (IRR: 0.91; [95% CI 0.66 to 1.27]; p = 0.60; I 2 = 0%). Regarding the remaining outcomes, data were heterogeneous and showed no clear difference. In premenopausal women, the use of third- and fourth-generation oral contraceptives is associated with an improved lipid profile and lower risk of arterial thrombosis. Data were inconclusive regarding the rest of outcomes assessed. This review was registered in PROSPERO with CRD42020211133.

BACKGROUND: Functional gallbladder disorder is most commonly defined by biliary colic and low ejection fraction (EF) on cholescintigraphy. Biliary hyperkinesia is a controversial type of functional gallbladder disorder, and its definition and the role of cholecystectomy in treating functional gallbladder disorder remains unclear. STUDY DESIGN: We conducted a retrospective review of patients who underwent cholecystokinin-stimulated cholescintigraphy and cholecystectomy at 3 Mayo Clinic sites between 2007 and 2020. Eligible patients were 18 years or older, presented with symptoms of biliary disease, had an EF greater than 50%, underwent cholecystectomy, and had no evidence of acute cholecystitis or cholelithiasis on imaging. We used receiver operating characteristics curve analysis to identify the optimal cutoff value that predicted symptom resolution within 30 days of cholecystectomy. RESULTS: A total of 2,929 cholecystokinin-stimulated cholescintigraphy scans were performed during the study period; the average EF was 67.5% and the median EF was 77%. Analyzing those with EFs greater than or equal to 50% yielded 1,596 patients with 141 (8.8%) going on to have cholecystectomy. No significant differences were found in age, sex, BMI, final pathology between patients with and without pain resolution. Using a cutoff EF of 81% was significantly associated with pain resolution after cholecystectomy (78.2% for EF greater than or equal to 81% vs 60.0% for EF less than 81%, p = 0.03). Chronic cholecystitis was found in 61.7% of the patients on final pathology. CONCLUSIONS: We determined that an EF cutoff of 81% is a reasonable upper limit of normal gallbladder EF. Patients with biliary symptoms and an EF greater than 81% but no evidence of biliary disease on ultrasound or scintigraphy can be classified as having biliary hyperkinesia. Based on our findings, we recommend cholecystectomy for this patient population.

PURPOSE Erb-B2 receptor tyrosine kinase 2 ( ERBB2)–positive breast cancer (BC) is particularly common in young women. Genomic features of ERBB2-positive tumors before and after chemotherapy and trastuzumab (chemo + H) have not been described in young women and are important for guiding study of therapeutic resistance in this population. METHODS From a large prospective cohort of women age 40 years or younger with BC, we identified patients with ERBB2-positive BC and tumor tissue available before and after chemo + H. Whole-exome sequencing (WES) was performed on each tumor and on germline DNA from blood. Tumor-normal pairs were analyzed for mutations and copy number (CN) changes. RESULTS Twenty-two women had successful WES on samples from at least one time point; 12 of these had paired sequencing results from before and after chemo + H and 10 had successful sequencing from either time point. TP53 was the only significantly recurrently mutated gene in both pre- and post-treatment samples. MYC gene amplification was observed in four post-treatment tumors. Seven of 12 patients with paired samples showed acquired and/or clonally enriched alterations in cancer-related genes. One patient had an increased clonality putative activating mutation in ERBB2. Another patient acquired a clonal hotspot mutation in TP53. Other genomic changes acquired in post-treatment specimens included alterations in NOTCH2, STIL, PIK3CA, and GATA3. There was no significant change in median ERBB2 CN (20.3 v 22.6; Wilcoxon P = .79) between paired samples. CONCLUSION ERBB2-positive BCs in young women displayed substantial genomic evolution after treatment with chemo + H. Approximately half of patients with paired samples demonstrated acquired and/or clonally enriched genomic changes in cancer genes. ERBB2 CN changes were uncommon. We identified several genes warranting exploration as potential mechanisms of resistance to therapy in this population.

Abstract There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder with oftentimes an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in bipolar disorder (BD). We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association with a subset of BD-I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement (response- emergent mania).

Background: The use of bone morphogenic protein and mesenchymal stem cells has shown promise in promoting bone regeneration in calvarial defects. However, a systematic review of the available literature is needed to evaluate the efficacy of this approach. Methods: We comprehensively searched electronic databases using MeSH terms related to skull defects, bone marrow mesenchymal stem cells, and bone morphogenic proteins. Eligible studies included animal studies that used BMP therapy and mesenchymal stem cells to promote bone regeneration in calvarial defects. Reviews, conference articles, book chapters, and non-English language studies were excluded. Two independent investigators conducted the search and data extraction. Results: Twenty-three studies published between 2010 and 2022 met our inclusion criteria after a full-text review of the forty-five records found in the search. Eight of the 23 studies used mice as models, while 15 used rats. The most common mesenchymal stem cell was bone marrow-derived, followed by adipose-derived. BMP-2 was the most popular. Stem cells were embedded in Scaffold (13), Transduction (7), and Transfection (3), and they were delivered BMP to cells. Each treatment used 2 × 104–1 × 107 mesenchymal stem cells, averaging 2.26 × 106. Most BMP-transduced MSC studies used lentivirus. Conclusions: This systematic review examined BMP and MSC synergy in biomaterial scaffolds or alone. BMP therapy and mesenchymal stem cells in calvarial defects, alone, or with a scaffold regenerated bone. This method treats skull defects in clinical trials. The best scaffold material, therapeutic dosage, administration method, and long-term side effects need further study.

Myocardial infarction (MI) secondary to thrombolytic therapy in the setting of acute ischaemic stroke (AIS) is a rare but severe complication. This phenomenon has been well documented in the past with recombinant tissue-type plasminogen activator, also known as Alteplase. However, there are no documented reports of MI secondary to Tenecteplase (TNKase), an alternative thrombolytic agent rapidly gaining favour in managing AIS. We report a male patient in his 50s who received TNKase for an AIS and subsequently developed an inferolateral ST elevation MI.

9069 Background: With the emergence of effective targeted-therapies for KRAS G12C, and the development of promising agents for KRAS G12V and G12D among others, the identity of unique KRAS mutations in non-small cell lung cancer (NSCLC) has become increasingly relevant. Acquired KRAS mutations are a known mechanism of resistance observed across driver mutation-positive (DM+) NSCLC. The incidence and diversity of these acquired alterations, and whether they differ from those observed in de novo KRAS-mutated NSCLC, is unknown. Methods: NSCLC molecular profiles were obtained using next-generation sequencing (Caris Life Sciences) with paired whole-transcriptomic sequencing (Illumina NovaSeq) and immunohistochemistry (Caris Life Sciences). Demographic data were abstracted from medical records. KRAS mutation diversity was defined for de novo KRAS-mutated ( KRASmt) NSCLC ( KRAS as only identified driver – KRASmt_dn) and DM+ NSCLC with acquired KRAS mutations (concurrent KRASmt with other known driver – KRASmt_acq). Fisher’s exact test was used to compare the distribution of unique KRAS mutations between the groups. Due to the unique biology of NSCLC with class II/III BRAF mutations, this subset was removed from the KRASmt_acq subgroup for the final analysis. Results: A total of 5932 KRASmt NSCLC samples were identified, among which 5879 were KRASmt_dn and 53 were KRASmt_acq (see table). The distribution of unique KRAS mutations was not significantly different between groups (p = 0.14). Within the KRASmt_dn group, KRAS G12C was most common (40%), followed by G12V (19%), G12D (14%), G12A (7%) and Q61H/G13C (4% each). In the KRASmt_acq group, KRAS G12C was most common (30%), followed by G12D (19%), G12V (17%), Q61H (11%), G12A (7%), and G13C (6%). The most common observed driver mutations in the KRASmt_acq group were EGFR (38%) and MET (30%). In the EGFR group, KRAS G12D (25%), Q61H/G12C (20% each), G12V/G13C (10% each), and G12F/A/R (5% each) were observed. In the MET group, KRAS G12C (25%), G12D/V/A (19% each), Q61H (12%) and G12S (6%) were seen. Among 7 patients with a documented history of smoking in the KRASmt_acq group, KRAS G12D and Q61H were most common (29% each), followed by G12V/F and G13C (14% each). Conclusions: While the distribution of unique KRAS mutations did not differ significantly between KRASmt_dn and KRASmt_acq groups, acquired KRAS mutations were seen across DM+ NSCLC subsets, among which the frequency of observed mutations appeared to vary. The functional and immunological significance of these mutations, and their impact on clinical outcomes, warrants further investigation. [Table: see text]