A protein kinase C α and ß inhibitor blunts hyperphagia to halt renal function decline and reduces adiposity in a rat model of obesity-driven type 2 diabetes.

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences for afflicted individuals. The disease can be difficult to control, and therapeutic strategies to prevent T2D-induced tissue and organ damage are needed. Here we describe the results of administering a potent and selective inhibitor of Protein Kinase C (PKC) family members PKCα and PKCß, Cmpd 1, in the ZSF1 obese rat model of hyperphagia-induced, obesity-driven T2D. Although our initial intent was to evaluate the effect of PKCα/ß inhibition on renal damage in this model setting, Cmpd 1 unexpectedly caused a marked reduction in the hyperphagic response of ZSF1 obese animals. This halted renal function decline but did so indirectly and indistinguishably from a pair feeding comparator group. However, above and beyond this food intake effect, Cmpd 1 lowered overall animal body weights, reduced liver vacuolation, and reduced inguinal adipose tissue (iWAT) mass, inflammation, and adipocyte size. Taken together, Cmpd 1 had strong effects on multiple disease parameters in this obesity-driven rodent model of T2D. Further evaluation for potential translation of PKCα/ß inhibition to T2D and obesity in humans is warranted.

The SUPER reporting guideline suggested for reporting of surgical technique.

Background: Existing reporting guidelines pay insufficient attention to the detail and comprehensiveness reporting of surgical technique. The Surgical techniqUe rePorting chEcklist and standaRds (SUPER) aims to address this gap by defining reporting standards for surgical technique. The SUPER guideline intends to apply to articles that encompass surgical technique in any study design, surgical discipline, and stage of surgical innovation. Methods: Following the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network approach, 16 surgeons, journal editors, and methodologists reviewed existing reporting guidelines relating to surgical technique, reviewed papers from 15 top journals, and brainstormed to draft initial items for the SUPER. The initial items were revised through a three-round Delphi survey from 21 multidisciplinary Delphi panel experts from 13 countries and regions. The final SUPER items were formed after an online consensus meeting to resolve disagreements and a three-round wording refinement by all 16 SUPER working group members and five SUPER consultants. Results: The SUPER reporting guideline includes 22 items that are considered essential for good and informative surgical technique reporting. The items are divided into six sections: background, rationale, and objectives (items 1 to 5); preoperative preparations and requirements (items 6 to 9); surgical technique details (items 10 to 15); postoperative considerations and tasks (items 16 to 19); summary and prospect (items 20 and 21); and other information (item 22). Conclusions: The SUPER reporting guideline has the potential to guide detailed, comprehensive, and transparent surgical technique reporting for surgeons. It may also assist journal editors, peer reviewers, systematic reviewers, and guideline developers in the evaluation of surgical technique papers and help practitioners to better understand and reproduce surgical technique. Trial Registration: https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-other-study-designs/#SUPER.

The SUPER reporting guideline suggested for reporting of surgical technique: explanation and elaboration.

Background: Surgical technique plays an essential role in achieving good health outcomes. However, the quality of surgical technique reporting remains heterogeneous. Reporting checklists could help authors to describe the surgical technique more transparently and effectively, as well as to assist reviewers and editors evaluate it more informatively, and promote readers to better understand the technique. We previously developed SUPER (surgical technique reporting checklist and standards) to assist authors in reporting their research that contains surgical technique more transparently. However, further explanation and elaboration of each item are needed for better understanding and reporting practice. Methods: We searched surgical literature in PubMed, Google Scholar and journal websites published up to January 2023 to find multidiscipline examples in various article types for each SUPER item. Results: We explain the 22 items of the SUPER and provide rationales item by item alongside. We provide 69 examples from 53 literature that present optimal reporting of the 22 items. Article types of examples include pure surgical technique, and case reports, observational studies and clinical trials that contain surgical technique. Examples are multidisciplinary, including general surgery, orthopaedical surgery, cardiac surgery, thoracic surgery, gastrointestinal surgery, neurological surgery, oncogenic surgery, and emergency surgery etc. Conclusions: Along with SUPER article, this explanation and elaboration file can promote deeper understanding on the SUPER items. We hope that the article could further guide surgeons and researchers in reporting, and assist editors and peer reviewers in reviewing manuscripts related to surgical technique.

Exogenous DNA enhances DUOX2 expression and function in human pancreatic cancer cells by activating the cGAS-STING signaling pathway.

Pro-inflammatory cytokines upregulate the expression of the H2O2-producing NADPH oxidase dual oxidase 2 (DUOX2)2 which, when elevated, adversely affects survival from pancreatic ductal adenocarcinoma (PDAC). Because the cGAS-STING pathway is known to initiate pro-inflammatory cytokine expression following uptake of exogenous DNA, we examined whether activation of cGAS-STING could play a role in the generation of reactive oxygen species by PDAC cells. Here, we found that a variety of exogenous DNA species markedly increased the production of cGAMP, the phosphorylation of TBK1 and IRF3, and the translocation of phosphorylated IRF3 into the nucleus, leading to a significant, IRF3-dependent enhancement of DUOX2 expression, and a significant flux of H2O2 in PDAC cells. However, unlike the canonical cGAS-STING pathway, DNA-related DUOX2 upregulation was not mediated by NF-κB. Although exogenous IFN-ß significantly increased Stat1/2-associated DUOX2 expression, intracellular IFN-ß signaling that followed cGAMP or DNA exposure did not itself increase DUOX2 levels. Finally, DUOX2 upregulation subsequent to cGAS-STING activation was accompanied by the enhanced, normoxic expression of HIF-1α and VEGF-A as well as DNA double strand cleavage, suggesting that cGAS-STING signaling may support the development of an oxidative, pro-angiogenic microenvironment that could contribute to the inflammation-related genetic instability of pancreatic cancer.

Reporting guidelines for surgical technique could be improved: a scoping review and a call for action.

OBJECTIVES: To identify reporting guidelines related to surgical technique and propose recommendations for areas that require improvement. STUDY DESIGN AND SETTING: A protocol-guided scoping review was conducted. A literature search of MEDLINE, the EQUATOR Network Library, Google Scholar, and Networked Digital Library of Theses and Dissertations was conducted to identify surgical technique reporting guidelines published up to December 31, 2021. RESULTS: We finally included 55 surgical technique reporting guidelines, vascular surgery (n = 18, 32.7%) was the most common among the clinical specialties covered. The included guidelines generally showed a low degree of international and multidisciplinary cooperation. Few guidelines provided a detailed development process (n = 14, 25.5%), conducted a systematic literature review (n = 13, 23.6%), used the Delphi method (n = 4, 7.3%), or described post-publication strategy (n = 6, 10.9%). The vast majority guidelines focused on the reporting of intraoperative period (n = 50, 90.9%). However, of the guidelines requiring detailed descriptions of surgical technique methodology (n = 43, 78.2%), most failed to provide guidance on what constitutes an adequate description. CONCLUSION: Our study demonstrates significant deficiencies in the development methodology and practicality of reporting guidelines for surgical technique. A standardized reporting guideline that is developed rigorously and focuses on details of surgical technique may serve as a necessary impetus for change.

Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

Intrathecal sc-AAV9-CB-GFP: Systemic Distribution Predominates Following Single-Dose Administration in Cynomolgus Macaques.

Biodistribution of self-complementary adeno-associated virus-9 (scAAV9)-chicken ß-actin promoter-green fluorescent protein (GFP) was assessed in juvenile cynomolgus macaques infused intrathecally via lumbar puncture or the intracisterna magna (1.0×1013 or 3.0×1013 vg/animal), with necropsy 28 days later. Our results characterized central nervous system biodistribution compared with systemic organs/tissues by droplet digital polymerase chain reaction for DNA and in situ hybridization. Green fluorescent protein expression was characterized by Meso Scale Discovery electrochemiluminescence immunosorbent assay and immunohistochemistry (IHC). Biodistribution was widespread but variable, with vector DNA and GFP expression greatest in the spinal cord, dorsal root ganglia (DRG), and certain systemic tissues (e.g., liver), with low concentrations in many brain regions despite direct cerebrospinal fluid administration. Transduction and expression were observed primarily in perivascular astrocytes in the brain, with a paucity in neurons. Greater GFP expression was observed in hepatocytes, striated myocytes, cardiomyocytes, spinal cord lower motor neurons, and DRG sensory neurons by IHC. These results should be considered when evaluating scAAV9-based intrathecal delivery with the current expression cassette as a modality for neurologic diseases that require widespread brain neuronal expression. This capsid/expression cassette combination may be better suited for diseases that express a secreted protein and/or do not require widespread brain neuronal transduction.

A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non-Small Cell Lung Cancer.

In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non-small cell lung cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08-178-01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08-178-01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08-178-01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08-178-01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08-178-01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification. SIGNIFICANCE: This study describes unique mechanisms of action of a new mutant-selective HER2 kinase inhibitor that reduces both kinase activity and protein levels of HER2 in lung cancer.

Clash of the -itises: An Unexpected Case of Sigmoid Colon Vasculitis.

Vasculitis is an inflammatory process of the blood vessels, characterized by leukocyte infiltration in the vessel wall and reactive damage to the mural structures. They have a wide clinical spectrum and can present in a localized or systemic manner. Colonic involvement primarily manifests as abdominal pain and rectal bleeding. Less commonly, it can be associated with colonic perforation or anastomotic leakage after colorectal surgery. We report a case of a 42-year-old man with a history of HIV and proctocolitis who presented with an unexpected vasculitis of the sigmoid colon.

Combination of Type I and Type II MET Tyrosine Kinase Inhibitors as Therapeutic Approach to Prevent Resistance.

MET-targeted therapies are clinically effective in MET-amplified and MET exon 14 deletion mutant (METex14) non-small cell lung cancers (NSCLCs), but their efficacy is limited by the development of drug resistance. Structurally distinct MET tyrosine kinase inhibitors (TKIs) (type I/II) have been developed or are under clinical evaluation, which may overcome MET-mediated drug resistance mechanisms. In this study, we assess secondary MET mutations likely to emerge in response to treatment with single-agent or combinations of type I/type II MET TKIs using TPR-MET transformed Ba/F3 cell mutagenesis assays. We found that these inhibitors gave rise to distinct secondary MET mutant profiles. However, a combination of type I/II TKI inhibitors (capmatinib and merestinib) yielded no resistant clones in vitro The combination of capmatinib/merestinib was evaluated in vivo and led to a significant reduction in tumor outgrowth compared with either MET inhibitor alone. Our findings demonstrate in vitro and in vivo that a simultaneous treatment with a type I and type II MET TKI may be a clinically viable approach to delay and/or diminish the emergence of on target MET-mediated drug-resistance mutations.

Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of EGFR-mutant lung cancer.

The clinical efficacy of epidermal growth factor receptor (EGFR)­targeted therapy in EGFR-mutant non­small cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR inhibitor resistance occurs through amplification of the human growth factor receptor (MET) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent EGFR mutation and MET amplification are historically thought to be codependent on the activation of both oncogenes. Hence, patients whose tumors harbor both alterations are commonly treated with a combination of EGFR and MET tyrosine kinase inhibitors (TKIs). Here, we identify and characterize six patient-derived models of EGFR-mutant, MET-amplified lung cancer that have switched oncogene dependence to rely exclusively on MET activation for survival. We demonstrate in this MET-driven subset of EGFR TKI-refractory cancers that canonical EGFR downstream signaling was governed by MET, even in the presence of sustained mutant EGFR expression and activation. In these models, combined EGFR and MET inhibition did not result in greater efficacy in vitro or in vivo compared to single-agent MET inhibition. We further identified a reduced EGFR:MET mRNA expression stoichiometry as associated with MET oncogene dependence and single-agent MET TKI sensitivity. Tumors from 10 of 11 EGFR inhibitor­resistant EGFR-mutant, MET-amplified patients also exhibited a reduced EGFR:MET mRNA ratio. Our findings reveal that a subset of EGFR-mutant, MET-amplified lung cancers develop dependence on MET activation alone, suggesting that such patients could be treated with a single-agent MET TKI rather than the current standard-of-care EGFR and MET inhibitor combination regimens.

Developing the surgical technique reporting checklist and standards: a study protocol.

BACKGROUND: Standardized and transparent reporting of surgical technique is the cornerstone of effective dissemination, implementation and improvement. However, current reporting of surgical techniques is inadequate. The existing guidelines potentially applied to guide surgical technique reporting are with a minimal highlight of the surgical technique, lack requirements explaining what extent and dimensions need to be described in detail, or are unlikely to extrapolate to a wide range of surgical techniques. This study aims to formulate a rigorous protocol to develop a surgical technique reporting checklist and standards (SUPER) that defines what a clear, comprehensive and detailed surgical technique report should be contained. METHODS: This protocol is designed following the classic guidance for developing reporting guidelines recommended by the EQUATOR network. RESULTS: The development team will consist of surgeons (~80%), methodologists, and journal editors. The draft checklist sources will include a scoping review of existing reporting guidelines related to surgical technique, surgical technique articles from 15 top journals published in the last year, and brainstorming by the multidisciplinary development team. The final SUPER checklist will be formed after three rounds of Delphi surveys, one round of face-to-face meeting, and a month-long pilot test. The SUPER checklist will be published as open-access and be used in combination with existing reporting guidelines related to surgical techniques (e.g., IDEAL). This protocol will steer the SUPER checklist's development, allowing us to further elaborate surgical technique reporting for all surgical specialties, and enabling a more favorable experience for surgeons, nurses, medical students, residents, editors, and reviewers. TRIAL REGISTRATION: This trial is registered at the EQUATOR network on December 18th, 2020. Available at: https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-other-study-designs/.

Evidence on reporting guidelines for surgical technique in clinical disciplines: a scoping review protocol.

BACKGROUND: The reporting of surgical techniques is of mixed quality, with most at a very minimal level. Reporting guidelines that could be applied to guide surgical technique reporting vary in methodology for development, discipline coverage, dimension coverage and detail requested. However, a scoping review that could indicate the gaps and efforts needed in surgical technique reporting guidelines is lacking and warranted. This study aims to design a methodological rigour protocol to guide the development of a scoping review of surgical technique reporting guidelines. METHODS: This protocol is designed following the 2020 manual proposed by the Joanna Briggs Institute. To further ensure the soundness of the protocol, we also included multidisciplinary professionals (including methodologists, clinicians, and journal editors) to refine the protocol. DISCUSSION: Seven key steps for developing the scoping review are identified and presented in detail, including (I) identifying the research questions; (II) inclusion criteria; (III) search strategy; (IV) source of evidence selection; (V) data extraction; (VI) analysis of the evidence; and (VII) presentation of the results. Guided by this protocol, the subsequent scoping review will inform us the overview of surgical technique reporting guidelines and precisely guide our direction and next steps in improving surgical technique reporting guidelines. TRIAL REGISTRATION: This protocol is not registered as the PROSPERO database only accepts registration of systematic review protocols while does not accept registration of scoping review protocols.

Optical-Waveguide Based Tactile Sensing for Surgical Instruments of Minimally Invasive Surgery.

In recent years, with the rapid development of minimally invasive surgery (MIS), the lack of force sensing associated with the surgical instrument used in MIS has been increasingly a desirable technology amongst clinicians. However, it is still an open technical challenge to date since most existing tactile sensing principles are not suitable to small 3-dimensional (3D) curved surfaces often seen in surgical instruments, and as a result multi-point force detection cannot be realized. In this paper, a novel optical waveguide-based sensor was proposed to deal with the above research gap. A sensor prototype for curved surfaces resembling the surface of dissection forceps was developed and experimentally evaluated. The static parameters and dynamic response characteristics of the sensor were measured. Results show that the static hysteresis error is less than 3%, the resolution is 0.026 N, and the repeatability is less than 1.5%. Under a frequency of 12.5 Hz, the sensor could quickly measure the variation of the force signal. We demonstrated that this small and high-precision sensitive sensor design is promising to be used for creating multiple-point tactile sensing for minimally invasive surgical instruments with 3D surfaces.

Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406).

PURPOSE: BRAFV600E mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of BRAFV600E by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. METHODS: One hundred six patients with BRAFV600E-mutated metastatic CRC previously treated with one or two regimens were randomly assigned to irinotecan and cetuximab with or without vemurafenib (960 mg PO twice daily). RESULTS: Progression-free survival, the primary end point, was improved with the addition of vemurafenib (hazard ratio, 0.50, P = .001). The response rate was 17% versus 4% (P = .05), with a disease control rate of 65% versus 21% (P < .001). A decline in circulating tumor DNA BRAFV600E variant allele frequency was seen in 87% versus 0% of patients (P < .001), with a low incidence of acquired RAS alterations at the time of progression. RNA profiling suggested that treatment benefit did not depend on previously established BRAF subgroups or the consensus molecular subtype. CONCLUSION: Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in BRAFV600E-mutated CRC.

Mixed Serous and Clear Cell Adenocarcinoma of the Ovary Presenting with Symptomatic Hypercalcemia: A Case Report and Clinical Considerations.

INTRODUCTION: Hypercalcemia is a common phenomenon in patients with cancer but is more common among certain cancer types. Hypercalcemia in ovarian cancer is the common presenting sign in small cell carcinoma of the ovary, hypercalcemic type; however, there are no known documented cases of hypercalcemia as the presenting sign for mixed serous and clear cell adenocarcinoma. This case report describes symptomatic hypercalcemia as the presenting sign of mixed serous and clear cell carcinoma of the ovary. CASE PRESENTATION: A 60-year-old woman with a medical history of hypertension and hyperlipidemia presented to the outpatient clinic with weakness, nausea, emesis, constipation, and an unintended 9-kg (20-lb) weight loss. Her calcium level was elevated at 15.7 mg/dL (reference range = 8.5-10.3 mg/dL). She was treated for hypercalcemia and subsequently admitted to the hospital 4 times because of recurrence of symptoms. On outpatient workup, she was noted to have an abnormal positron emission tomography scan showing intense activity in the uterus consistent with malignancy. An exploratory laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and lymph node staging was performed, and pathologic findings demonstrated high-grade ovarian carcinoma with serous and clear cell features. DISCUSSION: Hypercalcemia is a rare but possible primary presenting symptom of ovarian cancer. In these patients, serum calcium measurements could possibly serve as a tumor marker for disease.

Effect of Weight Loss on Upper Airway Anatomy and the Apnea-Hypopnea Index. The Importance of Tongue Fat.

Rationale: Obesity is the primary risk factor for obstructive sleep apnea (OSA). Tongue fat is increased in obese persons with OSA, and may explain the relationship between obesity and OSA. Weight loss improves OSA, but the mechanism is unknown.Objectives: To determine the effect of weight loss on upper airway anatomy in subjects with obesity and OSA. We hypothesized that weight loss would decrease soft tissue volumes and tongue fat, and that these changes would correlate with reductions in apnea-hypopnea index (AHI).Methods: A total of 67 individuals with obesity and OSA (AHI ≥ 10 events/h) underwent a sleep study and upper airway and abdominal magnetic resonance imaging before and after a weight loss intervention (intensive lifestyle modification or bariatric surgery). Airway sizes and soft tissue, tongue fat, and abdominal fat volumes were quantified. Associations between weight loss and changes in these structures, and relationships to AHI changes, were examined.Measurements and Main Results: Weight loss was significantly associated with reductions in tongue fat and pterygoid and total lateral wall volumes. Reductions in tongue fat were strongly correlated with reductions in AHI (Pearson's rho = 0.62, P < 0.0001); results remained after controlling for weight loss (Pearson's rho = 0.36, P = 0.014). Reduction in tongue fat volume was the primary upper airway mediator of the relationship between weight loss and AHI improvement.Conclusions: Weight loss reduced volumes of several upper airway soft tissues in subjects with obesity and OSA. Improved AHI with weight loss was mediated by reductions in tongue fat. New treatments that reduce tongue fat should be considered for patients with OSA.

Longitudinal Associations Between Income Changes and Incident Cardiovascular Disease: The Atherosclerosis Risk in Communities Study.

Importance: Higher income is associated with lower incident cardiovascular disease (CVD). However, there is limited research on the association between changes in income and incident CVD. Objective: To examine the association between change in household income and subsequent risk of CVD. Design, Setting, and Participants: The Atherosclerosis Risk In Communities (ARIC) study is an ongoing, prospective cohort of 15 792 community-dwelling men and women, of mostly black or white race, from 4 centers in the United States (Jackson, Mississippi; Washington County, Maryland; suburbs of Minneapolis, Minnesota; and Forsyth County, North Carolina), beginning in 1987. For our analysis, participants were followed up until December 31, 2016. Exposures: Participants were categorized based on whether their household income dropped by more than 50% (income drop), remained unchanged/changed less than 50% (income unchanged), or increased by more than 50% (income rise) over a mean (SD) period of approximately 6 (0.3) years between ARIC visit 1 (1987-1989) and visit 3 (1993-1995). Main Outcomes and Measures: Our primary outcome was incidence of CVD after ARIC visit 3, including myocardial infarction (MI), fatal coronary heart disease, heart failure (HF), or stroke during a mean (SD) of 17 (7) years. Analyses were adjusted for sociodemographic variables, health behaviors, and CVD biomarkers. Results: Of the 8989 included participants (mean [SD] age at enrollment was 53 [6] years, 1820 participants were black [20%], and 3835 participants were men [43%]), 900 participants (10%) experienced an income drop, 6284 participants (70%) had incomes that remained relatively unchanged, and 1805 participants (20%) experienced an income rise. After full adjustment, those with an income drop experienced significantly higher risk of incident CVD compared with those whose incomes remained relatively unchanged (hazard ratio, 1.17; 95% CI, 1.03-1.32). Those with an income rise experienced significantly lower risk of incident CVD compared with those whose incomes remained relatively unchanged (hazard ratio, 0.86; 95% CI, 0.77-0.96). Conclusions and Relevance: Income drop over 6 years was associated with higher risk of subsequent incident CVD over 17 years, while income rise over 6 years was associated with lower risk of subsequent incident CVD over 17 years. Health professionals should have greater awareness of the influence of income change on the health of their patients.

Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor.

Allosteric kinase inhibitors offer a potentially complementary therapeutic strategy to ATP-competitive kinase inhibitors due to their distinct sites of target binding. In this study, we identify and study a mutant-selective EGFR allosteric inhibitor, JBJ-04-125-02, which as a single agent can inhibit cell proliferation and EGFRL858R/T790M/C797S signaling in vitro and in vivo. However, increased EGFR dimer formation limits treatment efficacy and leads to drug resistance. Remarkably, osimertinib, an ATP-competitive covalent EGFR inhibitor, uniquely and significantly enhances the binding of JBJ-04-125-02 for mutant EGFR. The combination of osimertinib and JBJ-04-125-02 results in an increase in apoptosis, a more effective inhibition of cellular growth, and an increased efficacy in vitro and in vivo compared with either single agent alone. Collectively, our findings suggest that the combination of a covalent mutant-selective ATP-competitive inhibitor and an allosteric EGFR inhibitor may be an effective therapeutic approach for patients with EGFR-mutant lung cancer. SIGNIFICANCE: The clinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutant lung cancer is limited by acquired drug resistance, thus highlighting the need for alternative strategies to inhibit EGFR. Here, we identify a mutant EGFR allosteric inhibitor that is effective as a single agent and in combination with the EGFR TKI osimertinib.This article is highlighted in the In This Issue feature, p. 813.

Efficacy and safety of spironolactone in the heart failure with mid-range ejection fraction and heart failure with preserved ejection fraction: A meta-analysis of randomized clinical trials.

BACKGROUND: Recent studies have shown the efficacy for using spironolactone to treat heart failure with reduced ejection fraction (HFrEF), but the efficacy of spironolactone for heart failure with mid-range ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) is unclear. This meta-analysis investigated the efficacy and safety of spironolactone in patients with HFmrEF and HFpEF. METHODS AND RESULTS: We searched several databases including PubMed and the Cochrane Collaboration, for randomized controlled trials (RCTs) that assessed spironolactone treatment in HFmrEF and HFpEF. Eleven RCTs including 4539 patients were included. Spironolactone reduced hospitalizations (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.73-0.95; P = .006), improved New York Heart Association functional classifications (NYHA-FC) (OR, 0.35; 95% CI, 0.19-0.66; P = .001), decreased the levels of brain natriuretic peptide (BNP) (mean difference [MD], - 44.80 pg/mL; 95% CI, -73.44--16.17; P = .002), procollagen type I C-terminal propeptide (PICP) (MD, -27.04 ng/mL; 95% CI, -40.77--13.32, P < .001) in HFmrEF and HFpEF. Besides, it improved 6-minute walking distances (6-MWD) (standard weighted mean difference [SMD], 0.45 m; 95% CI, 0.27-0.64; P < .001), decreased amino-terminal peptide of procollagen type-III (PIIINP) (SMD, -0.37 µg/L; 95% CI, -0.59--0.15; P = .001) in HFpEF only. The risks of hyperkalemia (P<.001) and gynecomastia (P<.001) were increased. CONCLUSION: Patients with HFmrEF and HFpEF could benefit from spironolactone treatment, with reduced hospitalizations, BNP levels, improved NYHA-FC, alleviated myocardial fibrosis by decreasing serum PICP in HFmrEF and HFpEF, decreased PIIINP levels and increased 6-MWD only in HFpEF. The risks of hyperkalemia and gynecomastia were significantly increased with the spironolactone treatment.