FGF10 mitigates doxorubicin-induced myocardial toxicity in mice via activation of FGFR2b/PHLDA1/AKT axis.

Doxorubicin is a common chemotherapeutic agent in clinic, but myocardial toxicity limits its use. Fibroblast growth factor (FGF) 10, a multifunctional paracrine growth factor, plays diverse roles in embryonic and postnatal heart development as well as in cardiac regeneration and repair. In this study we investigated the role of FGF10 as a potential modulator of doxorubicin-induced cardiac cytotoxicity and the underlying molecular mechanisms. Fgf10+/- mice and an inducible dominant negative FGFR2b transgenic mouse model (Rosa26rtTA; tet(O)sFgfr2b) were used to determine the effect of Fgf10 hypomorph or blocking of endogenous FGFR2b ligands activity on doxorubicin-induced myocardial injury. Acute myocardial injury was induced by a single injection of doxorubicin (25 mg/kg, i.p.). Then cardiac function was evaluated using echocardiography, and DNA damage, oxidative stress and apoptosis in cardiac tissue were assessed. We showed that doxorubicin treatment markedly decreased the expression of FGFR2b ligands including FGF10 in cardiac tissue of wild type mice, whereas Fgf10+/- mice exhibited a greater degree of oxidative stress, DNA damage and apoptosis as compared with the Fgf10+/+ control. Pre-treatment with recombinant FGF10 protein significantly attenuated doxorubicin-induced oxidative stress, DNA damage and apoptosis both in doxorubicin-treated mice and in doxorubicin-treated HL-1 cells and NRCMs. We demonstrated that FGF10 protected against doxorubicin-induced myocardial toxicity via activation of FGFR2/Pleckstrin homology-like domain family A member 1 (PHLDA1)/Akt axis. Overall, our results unveil a potent protective effect of FGF10 against doxorubicin-induced myocardial injury and identify FGFR2b/PHLDA1/Akt axis as a potential therapeutic target for patients receiving doxorubicin treatment.

FGF10 Therapeutic Administration Promotes Mobilization of Injury-Activated Alveolar Progenitors in a Mouse Fibrosis Model.

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with dire consequences and in urgent need of improved therapies. Compelling evidence indicates that damage or dysfunction of AT2s is of central importance in the development of IPF. We recently identified a novel AT2 subpopulation characterized by low SFTPC expression but that is enriched for PD-L1 in mice. These cells represent quiescent, immature AT2 cells during normal homeostasis and expand upon pneumonectomy (PNX) and were consequently named injury-activated alveolar progenitors (IAAPs). FGF10 is shown to play critical roles in lung development, homeostasis, and injury repair demonstrated in genetically engineered mice. In an effort to bridge the gap between the promising properties of endogenous Fgf10 manipulation and therapeutic reality, we here investigated whether the administration of exogenous recombinant FGF10 protein (rFGF10) can provide preventive and/or therapeutic benefit in a mouse model of bleomycin-induced pulmonary fibrosis with a focus on its impact on IAAP dynamics. C57BL/6 mice and SftpcCreERT2/+; tdTomatoflox/+ mice aged 8-10 weeks old were used in this study. To induce the bleomycin (BLM) model, mice were intratracheally (i.t.) instilled with BLM (2 µg/g body weight). BLM injury was induced after a 7-day washout period following tamoxifen induction. A single i.t. injection of rFGF10 (0.05 µg/g body weight) was given on days 0, 7, 14, and 21 after BLM injury. Then, the effects of rFGF10 on BLM-induced fibrosis in lung tissues were assessed by H&E, IHC, Masson's trichrome staining, hydroxyproline and Western blot assays. Immunofluorescence staining and flow cytometry was used to assess the dynamic behavior of AT2 lineage-labeled SftpcPos (IAAPs and mature AT2) during the course of pulmonary fibrosis. We observed that, depending on the timing of administration, rFGF10 exhibited robust preventive or therapeutic efficacy toward BLM-induced fibrosis based on the evaluation of various pathological parameters. Flow cytometric analysis revealed a dynamic expansion of IAAPs for up to 4 weeks following BLM injury while the number of mature AT2s was drastically reduced. Significantly, rFGF10 administration increased both the peak ratio and the duration of IAAPs expansion relative to EpCAMPos cells. Altogether, our results suggest that the administration of rFGF10 exhibits therapeutic potential for IPF most likely by promoting IAAP proliferation and alveolar repair.

Leaving No Stone Unturned: Factors Associated With Overturning Insurance Claim Denials for Urological Conditions in New York State.

INTRODUCTION: Denied health claims in New York State may be appealed by external review. After appeal, the denial can either be upheld or overturned. Regardless, an appeal process results in delays in care and can negatively impact patient health and practice efficiency. This study aimed to describe the epidemiology of New York State urological external appeals and assess factors associated with successful appeals. METHODS: The New York State External Appeals database was queried for 2019-2021 urological cases (N=408). Patient age, gender, decision year, appeal reason, diagnosis, treatment, and reference to American Urological Association were extracted. Annual appeal volume was analyzed by linear regression. Relationships between appeal outcomes and characteristics were analyzed by χ2 tests. Multivariate logistic regression analysis was used to identify factors related to overturns. RESULTS: Overall, 39.5% of denials in this data set were overturned. Appeal volume increased annually, with overturned cases increasing 244% (mean 29.5, P = .068). Of reviewers, 15.6% referenced American Urological Association guidelines in their decision. Appeals mostly involved ages 40-59 years (32.4%), inpatient stays (63.5%), and infections (32.4%). Female sex, age 80+, diagnosis of incontinence/lower urinary tract symptoms, treatment with home health care, medications, or surgical services, and not referencing American Urological Association guidelines were significantly associated with successful appeal. Referencing American Urological Association guidelines had 70% decreased odds of overturning denials. CONCLUSIONS: Our findings suggest that upon appeal of denied claims, practices may have a high chance of overturning an initial denial and this trend is rising. These findings will help serve as a reference for future external appeals research and urology policy and advocacy groups.

SDE2 integrates into the TIMELESS-TIPIN complex to protect stalled replication forks.

Protecting replication fork integrity during DNA replication is essential for maintaining genome stability. Here, we report that SDE2, a PCNA-associated protein, plays a key role in maintaining active replication and counteracting replication stress by regulating the replication fork protection complex (FPC). SDE2 directly interacts with the FPC component TIMELESS (TIM) and enhances its stability, thereby aiding TIM localization to replication forks and the coordination of replisome progression. Like TIM deficiency, knockdown of SDE2 leads to impaired fork progression and stalled fork recovery, along with a failure to activate CHK1 phosphorylation. Moreover, loss of SDE2 or TIM results in an excessive MRE11-dependent degradation of reversed forks. Together, our study uncovers an essential role for SDE2 in maintaining genomic integrity by stabilizing the FPC and describes a new role for TIM in protecting stalled replication forks. We propose that TIM-mediated fork protection may represent a way to cooperate with BRCA-dependent fork stabilization.

[Impact of abdominal moxibustion in a period of day from 7 am to 9 am on improvement in post-stroke lower limb spasticity and muscle architecture parameter].

OBJECTIVE: To compare the therapeutic effect on post-stroke lower limb spasticity between the combined treatment of abdominal moxibustion from 7 am to 9 am and rehabilitation training and the simple rehabilitation training. METHODS: A total of 100 patients with post-stroke lower limb spasticity were randomized into an observation group (50 cases, 3 cases dropped off) and a control group (50 cases, 4 cases dropped off ). In the control group, the basic treatment of internal medicine and rehabilitation training of the limbs were adopted. In the observation group, on the basis of the treatment in the control group, at the time zone from 7 am to 9 am, moxibustion on the abdomen with "eight-trigram" moxa box [the central moxa box accurately facing Shenque (CV 8)] was given, lasting for 2 h, once every two days. Both groups were treated for 6 weeks. Separately, before and after treatment, the score of Fugl-Meyer assessment of the lower extremity (FMA-LE) and the grade of modified Ashworth scale (MAS) of ankle joint were evaluated on the affected side in patients of the two groups. Muscle skeleton ultrasound (MSUS) was adopted to determine the first layer muscle thickness (MT) anterior to the tibia, the number of pennation angle (PA) and the length of muscle fibers in the medial head of gastrocnemius muscle on the affected side. Besides, after treatment, the therapeutic effect was evaluated in the two groups. RESULTS: After treatment, the score of FMA-LE and the grade of MAS of ankle joint on the affected side were both improved as compared with those before treatment in patients of the two groups (P<0.01, P<0.05). The improvements in the observation group were better than those in the control group (P<0.01, P<0.05). After treatment, MT anterior to the tibia, the number of PA and the length of muscle fibers in the medial head of gastrocnemius muscle on the affected side were all increased as compared with before treatment in patients of the two groups (P<0.01). The increase degree in the observation group was larger than that in the control group (P<0.01). The total effective rate was 93.6% (44/47) in the observation group, better than 80.4% (37/46) in the control group (P<0.05). CONCLUSION: The combined treatment of abdominal moxibustion from 7 am to 9 am and rehabilitation training effectively relieves post-stroke lower limb spasticity and improves the limb functions and muscle structure. The total effective rate of this combined treatment is better than that of simple rehabilitation training.