Persistence of SARS-CoV-2 colonization and high expression of inflammatory factors in cardiac tissue 6 months after COVID-19 recovery: a prospective cohort study.

Background: The presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in myocardial autopsy tissues has been observed in certain individuals with coronavirus disease 2019 (COVID-19). However, the duration of cardiac involvement remains uncertain among recovered COVID-19 patients. Our study aims to evaluate the long-term persistence of SARS-CoV-2 within cardiac tissue. Methods: We prospectively and consecutively evaluated the patients undergoing mitral valve replacement (MVR) and left atrial (LA) volume reduction surgery from May 25 to June 10, 2023 at our center, who had been approximately 6 months of recovery after Omicron wave. Patients tested positive for SARS-CoV-2 upon admission were excluded. The surgical LA tissue was collected in RNA preservation solution and stored at -80 ℃ immediately. Then SARS-CoV-2, interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) RNA expression in LA tissues were assessed through thrice-repeated reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses. Categorical variables were assessed using the Chi-square or Fisher's exact tests, and continuous variables was analyzed using the Mann-Whitney U test. Results: Nine of 41 patients were enrolled, all of whom tested negative for SARS-CoV-2 upon admission (two antigen and PCR tests). In four of nine patients, SARS-CoV-2 RNA was detected in their LA tissue, indicating viral colonization. Among the four positive cases, the IL-6 and IL-1ß relative expression levels in the LA tissue of one patient were increased approximately 55- and 110-fold, respectively, compared to those of SARS-CoV-2 (-) patients. Increased expression of IL-6 and IL-1ß were observed in the myocardium of this patient. Another patient demonstrated a remarkable 7-fold increase in both IL-6 and IL-1ß expression, surpassing that of SARS-CoV-2 (-) patients. Additionally, no other cardiac inflammation-related diseases or conditions were presented in these two patients. The IL-6 and IL-1ß expression levels of the remaining two patients were not significantly different from those of SARS-CoV-2 (-) patients. The relative expression levels of IL-6 and IL-1ß in cardiac tissues of all SARS-CoV-2 (-) patients were relatively low. Interestingly, despite abnormally elevated levels of IL-6 and IL-1ß within their cardiac tissue, two patients did not show a significant increase in serum IL-6 and IL-1ß levels when compared to other patients. Conclusions: Our research suggests that certain COVID-19-recovered patients have persistent colonization of SARS-CoV-2 in their cardiac tissue, accompanied by a local increase in inflammatory factors.

A new minimal invasive technique with in-situ stent-graft fenestration for type A aortic dissection.

Background: Aortic surgery successfully improves the prognosis of patients with type A aortic dissection. However, total arch replacement and reconstruction remain challenging. This study presents a new surgical modality, the in-situ stent-graft fenestration (ISSF) technique, for simplifying aortic arch reconstruction and assesses its short-term efficacy and safety in patients with type A aortic dissection. Methods: Data from 177 patients with type A aortic dissection who underwent aortic arch reconstruction were retrospectively analyzed. Sun's procedure was performed in 90 patients and ISSF was performed in the other 87. Results: The in-hospital mortality rate was 7.8% in the Sun's procedure group and 3.4% in the ISSF group (p = 0.357). Compared to the Sun's procedure group, the ISSF group had significantly shorter surgical duration, cardiopulmonary bypass time, circulatory arrest time, mechanical ventilation time, and aortic cross-clamp time (p < 0.05). Additionally, intraoperative blood loss was lower in the ISSF group than in the Sun's procedure group (p < 0.05). Patients who underwent ISSF also had a lower incidence of postoperative complications, including lung injury, renal failure, peripheral nerve injury, and chylothorax, than those who underwent Sun's procedure (p < 0.05). During the 6-month follow-up period after surgery, both groups showed significant improvements in the true lumen diameter of the descending thoracic aorta post-operation compared with the pre-operation measurements; meanwhile, the false lumen diameter decreased (p < 0.05). Conclusions: The ISSF technique appears to be an effective and safe alternative to conventional surgical procedures for patients with type A aortic dissection, with the potential to simplify the procedure, shorten the operation time, and yield satisfactory operative results. However, further investigation is needed to determine its long-term benefits.

Systematic review of the effect of cerebrospinal fluid drainage on outcomes after endovascular type B aortic dissection repair.

OBJECTIVE: The aim of the present systematic review was to determine whether prophylactic use of cerebrospinal fluid drainage (CSFD) contributes to a lower rate of spinal cord ischemia (SCI) after thoracic endovascular aortic repair (TEVAR) for type B aortic dissection (TBAD). METHODS: PubMed, Embase, Web of Science and Cochrane Library databases were systematically searched to identify all relevant studies reported before May 7, 2023. A systematic review was conducted in accordance with PRISMA guidelines (PROSPERO registration no. CRD42023441392). The primary outcome was permanent SCI. Secondary outcomes were temporary SCI and 30-day/in-hospital mortality. The data were presented as the pooled event rates (ERs) and 95% confidence intervals (CIs). RESULTS: A total of 1008 studies were screened, of which 34 studies with 2749 patients were included in the present analysis. The mean Downs and Black quality assessment score was 8.71 (range, 5-12). The pooled rate of permanent SCI with prophylactic CSFD was identical to that without prophylactic CSFD (2.0%; 95% CI, 1.0-3.0; P = 0.445). No statistically significant difference was found between the rates of permanent SCI with routine vs. selective prophylactic CSFD (P = 0.596). The pooled rate of temporary SCI was 1.0% (95% CI, 0.00-1.0%). The pooled rate for 30-day or in-hospital mortality was not significantly different (P = 0.525) in patients with prophylactic CSFD (4.0, 95% CI 2.0-6.0) or without prophylactic CSFD (5.0, 95% CI 2.0-7.0). CONCLUSIONS: The systematic review has shown that prophylactic CSFD was not associated with a lower rate of permanent SCI and 30-day or in-hospital mortality after TEVAR for TBAD.

Early outcome of simplified total arch reconstruction under mild hypothermia (30-32 °C) with distal aortic perfusion.

OBJECTIVE: We designed a simplified total arch reconstruction (s-TAR) technique which could be performed under mild hypothermia (30-32 °C) with distal aortic perfusion. This study aimed to compare its efficacy of organ protection with the conventional total arch reconstruction (c-TAR). METHODS: We reviewed the clinical data of 195 patients who had ascending aortic aneurysm with extended aortic arch dilation and underwent simultaneous ascending aorta replacement and TAR procedure between January 2018 and December 2022 in our center. 105 received c-TAR under moderate hypothermia (25-28 °C) with circulatory arrest (c-TAR group); rest 90 received s-TAR under mild hypothermia (30-32 °C) with distal aortic perfusion (s-TAR group). RESULTS: The s-TAR group demonstrated shorter CPB time, cross-clamp time and lower body circulatory arrest time compared with the c-TAR group. The 30-day mortality was 2.9% for the c-TAR group and 1.1% for the s-TAR group (P = 0.043). The mean duration of mechanical ventilation was shorter in the s-TAR group. Paraplegia was observed in 4 of 105 patients (3.8%) in the c-TAR group, while no such events were observed in the s-TAR group. The incidence of temporary neurologic dysfunction was significantly higher in the c-TAR group. The incidence of permanent neurologic dysfunction also showed a tendency to be higher in the c-TAR group, without statistical significance. Furthermore, the incidence of reoperation for bleeding were significantly lower in the s-TAR group. The rate of postoperative hepatic dysfunction and all grades of AKI was remarkably lower in the s-TAR group. The 3-year survival rate was 95.6% in the s-TAR group and 91.4% in the c-TAR group. CONCLUSIONS: s-TAR under mild hypothermia (30-32℃) with distal aortic perfusion is associated with lower mortality and morbidity, offering better neurological and visceral organ protection compared with c-TAR.

A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress.

Mitochondria play essential roles in cancer cell adaptation to hypoxia, but the underlying mechanisms remain elusive. Through mitochondrial proteomic profiling, we here find that the prolyl hydroxylase EglN1 (PHD2) accumulates on mitochondria under hypoxia. EglN1 substrate-binding region in the ß2ß3 loop is responsible for its mitochondrial translocation and contributes to breast tumor growth. Furthermore, we identify AMP-activated protein kinase alpha (AMPKα) as an EglN1 substrate on mitochondria. The EglN1-AMPKα interaction is essential for their mutual mitochondrial translocation. After EglN1 prolyl-hydroxylates AMPKα under normoxia, they rapidly dissociate following prolyl-hydroxylation, leading to their immediate release from mitochondria. In contrast, hypoxia results in constant EglN1-AMPKα interaction and their accumulation on mitochondria, leading to the formation of a Ca2+ /calmodulin-dependent protein kinase 2 (CaMKK2)-EglN1-AMPKα complex to activate AMPKα phosphorylation, ensuring metabolic homeostasis and breast tumor growth. Our findings identify EglN1 as an oxygen-sensitive metabolic checkpoint signaling hypoxic stress to mitochondria through its ß2ß3 loop region, suggesting a potential therapeutic target for breast cancer.

A cleaved METTL3 potentiates the METTL3-WTAP interaction and breast cancer progression.

N6-methyladenosine (m6A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms' tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3). We find that METTL3a is required for the METTL3-WTAP interaction, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A deposition, and METTL3a mediates mammalian target of rapamycin (mTOR) activation via m6A-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.

FDXR drives primary and endocrine-resistant tumor cell growth in ER+ breast cancer via CPT1A-mediated fatty acid oxidation.

Background: The majority of breast cancers (BCs) expressing estrogen receptor (ER) have shown endocrine resistance. Our previous study demonstrated that ferredoxin reductase (FDXR) promoted mitochondrial function and ER+ breast tumorigenesis. But the underlying mechanism is not clear. Methods: Liquid chromatography (LC) tandem mass spectrometry (MS/MS)-based metabolite profiling was utilized to reveal the metabolites regulated by FDXR. RNA microarray was utilized to determine the potential downstream targets of FDXR. Seahorse XF24 analyzer was performed to analyze the FAO-mediated oxygen consumption rate (OCR). Q-PCR and western blotting assays were used to measure expression levels of FDXR and CPT1A. MTS, 2D colony formation and anchorage-independent growth assays were used to evaluate the effects of FDXR or drug treatments on tumor cell growth of primary or endocrine-resistant breast cancer cells. Results: We found that depletion of FDXR inhibited fatty acid oxidation (FAO) by suppressing CPT1A expression. Endocrine treatment increased the expression levels of both FDXR and CPT1A. Further, we showed that depletion of FDXR or FAO inhibitor etomoxir treatment reduced primary and endocrine-resistant breast cancer cell growth. Therapeutically, combining endocrine therapy with FAO inhibitor etomoxir synergistically inhibits primary and endocrine-resistant breast cancer cell growth. Discussion: We reveal that the FDXR-CPT1A-FAO signaling axis is essential for primary and endocrine-resistant breast cancer cell growth, thus providing a potential combinatory therapy against endocrine resistance in ER+ breast cancer.

α-Ketoglutarate-dependent Enzymes in Breast Cancer and Therapeutic Implications.

α-Ketoglutarate (αKG)-dependent dioxygenases are a superfamily of enzymes that require oxygen, reduced iron, and αKG for their catalytic functions. Therefore, they have the potential to sense the availabilities of oxygen, iron, and specific metabolites, including αKG and its structurally related metabolites. These enzymes play essential roles in various biological processes, including cellular adaptation to hypoxia, epigenetic and epitranscriptomic regulation of gene expression, and metabolic reprogramming. Many αKG-dependent dioxygenases are dysregulated in cancer pathogenesis. Herein, we review how they are regulated and function in breast cancer, which may offer new therapeutic intervention strategies for targeting this family of enzymes.

Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury.

BACKGROUND AND AIMS: Sam50, a key component of the sorting and assembly machinery (SAM) complex, is also involved in bridging mitochondrial outer-membrane and inner-membrane contacts. However, the physiological and pathological functions of Sam50 remain largely unknown. APPROACH AND RESULTS: Here we show that Sam50 interacts with MICOS (mitochondrial contact site and cristae organizing system) and ATAD3 (ATPase family AAA domain-containing protein 3) to form the Sam50-MICOS-ATAD3-mtDNA axis, which maintains mtDNA stability. Loss of Sam50 causes mitochondrial DNA (mtDNA) aggregation. Furthermore, Sam50 cooperates with Mic60 to bind to cardiolipin, maintaining the integrity of mitochondrial membranes. Sam50 depletion leads to cardiolipin externalization, which causes mitochondrial outer-membrane and inner-membrane (including crista membrane) remodeling, triggering Bax mitochondrial recruitment, mtDNA aggregation, and release. Physiologically, acetaminophen (an effective antipyretic and analgesic)-caused Sam50 reduction or Sam50 liver-specific knockout induces mtDNA release, leading to activation of the cGAS-STING pathway and liver inflammation in mice. Moreover, exogenous expression of Sam50 remarkably attenuates APAP-induced liver hepatoxicity. CONCLUSIONS: Our findings uncover the critical role of Sam50 in maintaining mitochondrial membrane integrity and mtDNA stability in hepatocytes and reveal that Sam50 depletion-induced cardiolipin externalization is a signal of mtDNA release and controls mtDNA-dependent innate immunity.

Case report: Multiple brain metastases of atrial myxoma: Clinical experience and literature review.

Myxoma is the most common type of benign cardiac tumor in adults, and it has a strong tendency to embolize or metastasize to distant organs. Patients with multiple brain metastases have rarely been seen in clinics; hence, standard treatment protocols for multimyxoma metastasis in the brain have not been established. We present the case of a 47-year-old female who had convulsions in the right hand and repeated seizures. Computed tomography revealed multiple tumor sites in her brain. Craniotomy was conducted to remove the tumor sites. However, recurrent brain tumors and unexpected cerebral infarctions occurred frequently shortly after the treatment because the cardiac myxoma had not been treated due to the patient's personal concerns. The myxoma was resected by gamma knife radiosurgery, and temozolomide was given prior to cardiac surgery. There has been no evidence of tumor recurrence from the 2 years following the surgery until the present. This case highlights the importance of prioritizing cardiac lesions over cerebral lesions; if a cerebral metastasis has been found, it is likely that the cardiac myxoma is already unstable, with high rates of spread and metastasis. Therefore, it is unwise to treat metastasis sites before the cardiac myxoma. Additionally, the case suggests that gamma knife radiosurgery combined with temozolomide is effective as treatment for multiple myxoma metastasis in the brain. Compared with conventional cerebral surgery, gamma knife radiosurgery is safer, causes less bleeding, and requires a shorter time for recovery.

Effect of High-Flow Nasal Cannula for Hypoxemia Following Sun's Procedure in Acute Aortic Dissection Type a Patients.

Background: Patients with acute aortic dissection type A (AADA) often have hypoxemia (partial pressure of oxygen [PaO2]/fraction of inspired oxygen [FiO2] <300 mmHg) before weaning in the intensive care unit (ICU). This study compared the efficacy of high-flow nasal cannula (HFNC) with that of conventional oxygen therapy (COT) in patients with AADA following Sun's procedure. Methods: The medical records of 87 adult patients with AADA who underwent Sun's procedure and met the inclusion criteria (PaO2/FiO2 <300 mmHg before weaning) were retrospectively analyzed. After surgery, 41 patients were treated with HFNC and 46 were treated with COT. The oxygenation level, FiO2, partial pressure of carbon dioxide, heart rate, respiratory rate, subjective discomfort, and reintubation rate were recorded. The difference in lung volume loss between the HFNC and COT groups was assessed using the radiological atelectasis score (chest radiograph) or calculated from three-dimensional (3D) reconstructed computed tomography (CT) images. Results: From day 1 to day 5 after weaning, there was no significant difference in PaO2/FiO2 between the HFNC and COT groups, although the FiO2 was significantly lower in the HFNC group than in the COT group (P < 0.05). Further studies indicated that the percentage of lung volume loss (pleural effusion and/or pulmonary atelectasis) by 3D reconstruction of CT images at 4-8 days post-operation was significantly lower in the HFNC group (P < 0.05). The subjective experience of breathing discomfort, reintubation rate, and length of stay in the ICU were significantly reduced in the HFNC group (P < 0.05). There was no significant difference in readmission to the ICU and in-hospital mortality between the two groups. Conclusions: HFNC can be used as an effective oxygen therapy for AADA patients with hypoxemia after Sun's procedure.

OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development.

Many cancer cells maintain enhanced aerobic glycolysis due to irreversible defective mitochondrial oxidative phosphorylation (OXPHOS). This phenomenon, known as the Warburg effect, is recently challenged because most cancer cells maintain OXPHOS. However, how cancer cells coordinate glycolysis and OXPHOS remains largely unknown. Here, we demonstrate that OMA1, a stress-activated mitochondrial protease, promotes colorectal cancer development by driving metabolic reprogramming. OMA1 knockout suppresses colorectal cancer development in AOM/DSS and xenograft mice models of colorectal cancer. OMA1-OPA1 axis is activated by hypoxia, increasing mitochondrial ROS to stabilize HIF-1α, thereby promoting glycolysis in colorectal cancer cells. On the other hand, under hypoxia, OMA1 depletion promotes accumulation of NDUFB5, NDUFB6, NDUFA4, and COX4L1, supporting that OMA1 suppresses OXPHOS in colorectal cancer. Therefore, our findings support a role for OMA1 in coordination of glycolysis and OXPHOS to promote colorectal cancer development and highlight OMA1 as a potential target for colorectal cancer therapy.

PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis.

Mitophagy, which is a conserved cellular process for selectively removing damaged or unwanted mitochondria, is critical for mitochondrial quality control and the maintenance of normal cellular physiology. However, the precise mechanisms underlying mitophagy remain largely unknown. Prior studies on mitophagy focused on the events in the mitochondrial outer membrane. PHB2 (prohibitin 2), which is a highly conserved membrane scaffold protein, was recently identified as a novel inner membrane mitophagy receptor that mediates mitophagy. Here, we report a new signaling pathway for PHB2-mediated mitophagy. Upon mitochondrial membrane depolarization or misfolded protein aggregation, PHB2 depletion destabilizes PINK1 in the mitochondria, which blocks the mitochondrial recruitment of PRKN/Parkin, ubiquitin and OPTN (optineurin), leading to an inhibition of mitophagy. In addition, PHB2 overexpression directly induces PRKN recruitment to the mitochondria. Moreover, PHB2-mediated mitophagy is dependent on the mitochondrial inner membrane protease PARL, which interacts with PHB2 and is activated upon PHB2 depletion. Furthermore, PGAM5, which is processed by PARL, participates in PHB2-mediated PINK1 stabilization. Finally, a ligand of PHB proteins that we synthesized, called FL3, was found to strongly inhibit PHB2-mediated mitophagy and to effectively block cancer cell growth and energy production at nanomolar concentrations. Thus, our findings reveal that the PHB2-PARL-PGAM5-PINK1 axis is a novel pathway of PHB2-mediated mitophagy and that targeting PHB2 with the chemical compound FL3 is a promising strategy for cancer therapy.Abbreviations: AIFM1: apoptosis inducing factor mitochondria associated 1; ATP5F1A/ATP5A1: ATP synthase F1 subunit alpha; BAF: bafilomycin A1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CCCP: chemical reagent carbonyl cyanide m-chlorophenyl hydrazine; FL3: flavaglines compound 3; HSPD1/HSP60: heat shock protein family D (Hsp60) member 1; LC3B/MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryo fibroblasts; MPP: mitochondrial-processing peptidase; MT-CO2/COX2: mitochondrially encoded cytochrome c oxidase II; MTS: mitochondrial targeting sequence; OA: oligomycin and antimycin A; OPTN: optineurin; OTC: ornithine carbamoyltransferase; PARL: presenilin associated rhomboid like; PBS: phosphate-buffered saline; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PHB: prohibitin; PHB2: prohibitin 2; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; Roc-A: rocaglamide A; TOMM20: translocase of outer mitochondrial membrane 20; TUBB: tubulin beta class I.

Technical Improvements of Difficult Tracheotomy.

The aim of this study was to explore the application value of technical improvements of difficult tracheotomy. Percutaneous dilatational tracheotomy kit combined with traditional surgical tracheotomy was performed on seven patients with various types of difficult tracheotomy surgery from Jan. 2011 to Mar. 2013 in our hospital. The indicators, such as difficulty degree and intraoperative peripheral oxygen saturation changes of each patient, were assessed and analyzed. The average operating time was 20 min (from the beginning of skin incision to the implantation of the tracheal tube), and the time from cutting out tracheal cartilage rings to completely implanting tracheal tube was with 2 min; the intraoperative oxygen saturation degrees were all above 92 %. There were no serious complications, such as intraoperative hemorrhea, asphyxia, cardiac arrest, or others, and no complications, such as postoperative bleeding, pneumothorax, cervical spinal cord injury, tracheal stenosis, tracheoesophageal fistula, or others, appeared. The technical improvements used in difficult tracheotomy could reduce the risk of surgery, difficulties of the surgical operation and postoperative complications and make the operation much more easy and more suitable for the clinical application.