Differential cardiotoxic electrocardiographic response to doxorubicin treatment in conscious versus anesthetized mice.

Abstract Introduction Doxorubicin (DOX), an anticancer drug used in chemotherapy, causes significant cardiotoxicity. This study aimed to investigate the effects of DOX on mouse cardiac electrophysiology, in conscious versus anesthetized state. Methods Male and female C57BL/6 mice were injected with saline, 20 or 30 mg/kg DOX. ECGs were recorded 5 days post‐injection in conscious and isoflurane anesthetized states. ECGs were analyzed using a custom MATLAB software to determine P, PR, QRS, QTc, and RR intervals as well as heart rate variability (HRV). Results ECGs from the same mouse demonstrated P wave and QTc shortening as well as PR and RR interval prolongation in anesthetized versus conscious saline‐treated mice. ECG response to DOX was also modulated by anesthesia. DOX treatment induced significant ECG modulation in female mice alone. While DOX20 treatment caused decrease in P and QRS durations, DOX30 treatment‐induced QTc and RR interval prolongation in anesthetized but not in conscious female mice. These data suggest significant sex differences and anesthesia‐induced differences in ECG response to DOX. HRV measured in time and frequency domains, a metric of arrhythmia susceptibility, was increased in DOX20‐treated mice compared to saline. Conclusions This study for the first time identifies that the ECG response to DOX is modulated by anesthesia. Furthermore, this response demonstrated stark sex differences. These findings could have significant implications in clinical diagnosis of DOX cardiotoxicity

Stretchable and Transparent Metal Nanowire Microelectrodes for Simultaneous Electrophysiology and Optogenetics Applications

Recently developed optically transparent microelectrode technology provides a promising approach for simultaneous high-resolution electrical and optical biointerfacing with tissues in vivo and in vitro. A critically unmet need is designing high-performance stretchable platforms for conformal biointerfacing with mechanically active organs. Here, we report silver nanowire (Ag NW) stretchable transparent microelectrodes and interconnects that exhibit excellent electrical and electrochemical performance, high optical transparency, superior mechanical robustness and durability by a simple selective-patterning process. The fabrication method allows the direct integration of Ag NW networks on elastomeric substrates. The resulting Ag NW interface exhibits a low sheet resistance (Rsh) of 1.52–4.35 Ω sq−1, an advantageous normalized electrochemical impedance of 3.78–6.04 Ω cm2, a high optical transparency of 61.3–80.5% at 550 nm and a stretchability of 40%. The microelectrode arrays (MEAs) fabricated with this approach exhibit uniform electrochemical performance across all channels. Studies on mice demonstrate that both pristine and stretched Ag NW microelectrodes can achieve high-fidelity electrophysiological monitoring of cardiac activity with/without co-localized optogenetic pacing. Together, these results pave the way for developing stretchable and transparent metal nanowire networks for high-resolution opto-electric biointerfacing with mechanically active organs, such as the heart

Anthracycline cardiotoxicity is exacerbated by global p38β genetic ablation in a sexually dimorphic manner but unaltered by cardiomyocyte-specific p38α loss

Severe cardiotoxic effects limit the efficacy of doxorubicin (DOX) as a chemotherapeutic agent. Activation of intracellular stress signaling networks, including p38 mitogen-activated protein kinase (MAPK), has been implicated in DOX-induced cardiotoxicity (DIC). However, the roles of the individual p38 isoforms in DIC remain incompletely elucidated. We recently reported that global p38δ deletion protected female but not male mice from DIC, whereas global p38γ deletion did not significantly modulate it. Here we studied the in vivo roles of p38α and p38β in acute DIC. Male and female mice with cardiomyocyte-specific deletion of p38α or global deletion of p38β and their wild-type counterparts were injected with DOX. Survival and health were tracked for 10 days postinjection. Cardiac function was assessed by echocardiography and electrocardiography and fibrosis by Picrosirius red staining. Expression and activation of signaling proteins and inflammatory markers were measured by Western blot, phosphorylation array, and chemokine/cytokine array. Global p38β deletion significantly aggravated DIC and worsened cardiac electrical and mechanical function deterioration in female mice. Mechanistically, DIC in p38β-null female mice correlated with increased autophagy, sustained hyperactivation of proapoptotic JNK signaling, as well as remodeling of a myocardial inflammatory environment. In contrast, cardiomyocyte-specific deletion of p38α improved survival of DOX30-treated male mice 5 days posttreatment but did not influence cardiac function in DOX-treated male or female mice. Our data highlight the sex- and isoform-specific roles of p38α and p38β MAPKs in DOX-induced cardiac injury and suggest a novel in vivo function of p38β in protecting female mice from DIC. We show that p38α and p38β have distinct in vivo functions in a murine model of acute DIC. Specifically, although conditional cardiomyocyte-specific p38α deletion exhibited mild cardioprotective effects in male mice, p38β deletion exacerbated the DOX cardiotoxicity in female mice. Our findings caution against employing pyridinyl imidazole inhibitors that target both p38α and p38β isoforms as a cardioprotective strategy against DIC. Such an approach could have undesirable sex-dependent effects, including attenuating p38β-dependent cardioprotection in females

P38δ genetic ablation protects female mice from anthracycline cardiotoxicity

© 2020 the American Physiological Society. The efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOXinduced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38γ and p38δ, remain uncharacterized. We aimed to determine the potential cardioprotective effects of p38γ and p38δ genetic deletion in mice subjected to acute DOX treatment. Male and female wild-type (WT), p38γ-/-, p38δ-/-, and p38γ-/-δ-/- mice were injected with 30 mg/kg DOX and their survival was tracked for 10 days. During this period, cardiac function was assessed by echocardiography and electrocardiography and fibrosis by Picro Sirius Red staining. Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy. Significantly improved survival was observed in p38δ-/- female mice post-DOX relative to WT females, but not in p38γ-/- or p38γ-/-δ-/- male or female mice. The improved survival in DOX-treated p38δ-/- females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOXtreated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as suggested by increased LC3-II level, and decreased mammalian target of rapamycin activation was also observed in DOX-treated p38δ-/- females. p38δ plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38δ targeting could be a potential cardioprotective strategy in anthracycline chemotherapy. New & Noteworthy: This study for the first time identifies the sex-specific roles of the alternative p38γ and p38δ MAPK isoforms in promoting doxorubicin (DOX) cardiotoxicity. We show that p38δ and p38γ/δ systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOXtreated p38δ-/- females and autophagy marker was increased

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research