Effects of Phomopsidione on the Viability, Virulence, and Metabolites Profile of Methicillin-Resistant Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus (MRSA) infections have become one of the most threatening multidrug-resistant pathogens. Thus, an ongoing search for anti-MRSA compounds remains an urgent need to effectively treating MRSA infections. Phomopsidione, a novel antibiotic isolated from Diaporthe fraxini, has previously demonstrated potent anti-candidal activity. The present study aimed to investigate the effects of phomopsidione on the viability, virulence, and metabolites profile of MRSA. MRSA was sensitive to phomopsidione in a concentration-dependent manner. Phomopsidione exhibited minimum inhibitory concentration and minimum bactericidal concentration of 62.5 and 500.00 µg/mL against MRSA on broth microdilution assay. The compound showed significant reduction in virulence factors production including extracellular polymeric substances quantification, catalase, and lipase. An untargeted metabolomics analysis using liquid chromatography-high resolution mass spectrometry revealed a significant difference in the metabolites profile of MRSA with 13 putatively identified discriminant metabolites. The present study suggested the potential of phomopsidione as a promising anti-MRSA agent.

The Effect of Digital Mental Health Literacy Interventions on Mental Health: Systematic Review and Meta-Analysis.

BACKGROUND: Accelerated by technological advancements and the recent global pandemic, there is burgeoning interest in digital mental health literacy (DMHL) interventions that can positively affect mental health. However, existing work remains inconclusive regarding the effectiveness of DMHL interventions. OBJECTIVE: This systematic review and meta-analysis investigated the components and modes of DMHL interventions, their moderating factors, and their long-term impacts on mental health literacy and mental health. METHODS: We used a random-effects model to conduct meta-analyses and meta-regressions on moderating effects of DMHL interventions on mental health. RESULTS: Using 144 interventions with 206 effect sizes, we found a moderate effect of DMHL interventions in enhancing distal mental health outcomes (standardized mean difference=0.42, 95% CI -0.10 to 0.73; P<.001) and a large effect in increasing proximal mental health literacy outcomes (standardized mean difference=0.65, 95% CI 0.59-0.74; P<.001). Uptake of DMHL interventions was comparable with that of control conditions, and uptake of DMHL interventions did not moderate the effects on both proximal mental health literacy outcomes and distal mental health outcomes. DMHL interventions were as effective as face-to-face interventions and did not differ by platform type or dosage. DMHL plus interventions (DMHL psychoeducation coupled with other active treatment) produced large effects in bolstering mental health, were more effective than DMHL only interventions (self-help DMHL psychoeducation), and were comparable with non-DMHL interventions (treatment as usual). DMHL interventions demonstrated positive effects on mental health that were sustained over follow-up assessments and were most effective in enhancing the mental health of emerging and older adults. CONCLUSIONS: For theory building, our review and meta-analysis found that DMHL interventions are as effective as face-to-face interventions. DMHL interventions confer optimal effects on mental health when DMHL psychoeducation is combined with informal, nonprofessional active treatment components such as skills training and peer support, which demonstrate comparable effectiveness with that of treatment as usual (client-professional interactions and therapies). These effects, which did not differ by platform type or dosage, were sustained over time. Additionally, most DMHL interventions are found in Western cultural contexts, especially in high-income countries (Global North) such as Australia, the United States, and the United Kingdom, and limited research is conducted in low-income countries in Asia and in South American and African countries. Most of the DMHL studies did not report information on the racial or ethnic makeup of the samples. Future work on DMHL interventions that target racial or ethnic minority groups, particularly the design, adoption, and evaluation of the effects of culturally adaptive DMHL interventions on uptake and mental health functioning, is needed. Such evidence can drive the adoption and implementation of DMHL interventions at scale, which represents a key foundation for practice-changing impact in the provision of mental health resources for individuals and the community. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42023363995; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023363995.

Hypoglossal nerve delineation in nasopharyngeal carcinoma patients may reduce the radiation dose and damage to the nerve.

This study aims to establish a delineation guideline for the contouring of the hypoglossal nerve by dividing the nerve into different segments, and to test the possibility of a radiation dose reduction to the hypoglossal nerve in NPC patients receiving radiotherapy. Twenty NPC patients were selected arbitrarily. The hypoglossal nerves were delineated using anatomic landmarks and divided into the cisternal, intracanalicular, carotid, and transverse segments. The tumor coverage by radiation and dose-volume parameters of the nerve with and without various dose constraints to the hypoglossal nerve were compared. The hypoglossal nerve, which is invisible on CT images, can be delineated accurately with the assistance of several anatomic landmarks. Without a dose constraint to the hypoglossal nerve, the carotid space, intracanalicular, and transverse segments had high radiation dose-volumes. The dose-volume to the nerve, however, can be reduced when the nerve was defined and a dose constraint was given. The delineation of the hypoglossal nerve with its different segments is feasible. The carotid space, intracanalicular, and transverse segments received the highest dose, where the nerve damage was most likely located. The dose to the nerve can be reduced to less than 70 Gy using the intensity-modulated radiotherapy technique.

Non-invasive high frequency oscillatory ventilation inhibiting respiratory motion in healthy volunteers.

Precision radiotherapy needs to manage organ movements to prevent critical organ injury. The purpose of this study is to examine the feasibility of motion control of the lung by suppressing respiratory motion. The non-invasive high frequency oscillatory ventilation (NIHFOV) is a technique commonly used in the protection of lung for patients with acute lung disease. By using a very high respiratory frequency and a low tidal volume, NIHFOV allows gas exchange, maintains a constant mean airway pressure and minimizes the respiratory movements. We tested healthy volunteers NIHFOV to explore the optimal operational parameter setting and the best possible motion suppression achievable. This study was conducted with the approval of Institutional Review Boards of the Wuwei Cancer hospital (approval number: 2021-39) and carried out in accordance with Declaration of Helsinki. The study comprises two parts. Twenty three healthy volunteers participated in the first part of the study. They had 7 sessions of training with the NIHFOV. The duration of uninterrupted, continuous breathing under the NIHFOV and the optimal operational machine settings were defined. Eight healthy volunteers took part in the second part of the study and underwent 4-dimensional CT (4DCT) scanning with and without NIHFOV. Their respiratory waveform under free breathing (FB) and NIHFOV were recorded. The maximum range of motion of the diaphragm from the two scannings was compared, and the variation of bilateral lung volume was obtained to evaluate the impact of NIHFOV technique on lung volume. The following data were collected: comfort score, transcutaneous partial pressure of oxygen (PtcO2), transcutaneous partial pressure of carbon dioxide (PtcCO2), and pulse rate. Data with and without NIHFOV were compared to evaluate its safety, physiological impacts and effect of lung movement suppression. All the volunteers completed the training sessions eventlessly, demonstrating a good tolerability of the procedure. The median NIHFOV-on time was 32 min (22-45 min), and the maximum range of motion in the cephalic-caudal direction was significantly reduced on NIHFOV compared with FB (1.8 ± 0.8 cm vs 0.3 ± 0.1 cm, t = - 3.650, P = 0.003); the median range of motion was only 0.3 ± 0.1 cm on NIHFOV with a good reproducibility. The variation coefficient under NIHFOV of the right lung volume was 2.4% and the left lung volume was 9.2%. The PtcO2 and PtcCO2 were constantly monitored during NIHFOV. The medium PtcCO2 under NIHFOV increased lightly by 4.1 mmHg (interquartile range [IQR], 4-6 mmHg) compared with FB (t = 17.676, P < 0.001). No hypercapnia was found, PtcO2 increased significantly in all volunteers during NIHFOV (t = 25.453, P < 0.001). There was no significant difference in pulse rate between the two data sets (t = 1.257, P = 0.233). NIHFOV is easy to master in healthy volunteers to minimize respiratory movement with good tolerability and reproducibility. It is a feasible approach for lung motion control and could potentially be applied in accurate radiotherapy including carbon-ion radiotherapy through suppression of respiratory movement.

Diacetyl inhalation impairs airway epithelial repair in mice infected with influenza A virus.

Bronchiolitis obliterans (BO) is a debilitating disease of the small airways that can develop following exposure to toxic chemicals as well as respiratory tract infections. BO development is strongly associated with diacetyl (DA) inhalation exposures at occupationally relevant concentrations or severe influenza A viral (IAV) infections. However, it remains unclear whether lower dose exposures or more mild IAV infections can result in similar pathology. In the current work, we combined these two common environmental exposures, DA and IAV, to test whether shorter DA exposures followed by sublethal IAV infection would result in similar airways disease. Adult mice exposed to DA vapors 1 h/day for 5 consecutive days followed by infection with the airway-tropic IAV H3N2 (HKx31) resulted in increased mortality, increased bronchoalveolar lavage (BAL) neutrophil percentage, mixed obstruction and restriction by lung function, and subsequent airway remodeling. Exposure to DA or IAV alone failed to result in significant pathology, whereas mice exposed to DA + IAV showed increased α-smooth muscle actin (αSMA) and epithelial cells coexpressing the basal cell marker keratin 5 (KRT5) with the club cell marker SCGB1A1. To test whether DA exposure impairs epithelial repair after IAV infection, mice were infected first with IAV and then exposed to DA during airway epithelial repair. Mice exposed to IAV + DA developed similar airway remodeling with increased subepithelial αSMA and epithelial cells coexpressing KRT5 and SCGB1A1. Our findings reveal an underappreciated concept that common environmental insults while seemingly harmless by themselves can have catastrophic implications on lung function and long-term respiratory health when combined.

Ataxia telangiectasia mutated is required for efficient proximal airway epithelial cell regeneration following influenza A virus infection.

Children and young adults with mutant forms of ataxia telangiectasia mutated (ATM), a kinase involved in DNA damage signaling and mitochondrial homeostasis, suffer from recurrent respiratory infections, immune deficiencies, and obstructive airways disease associated with disorganized airway epithelium. We previously showed in mice how Atm was required to mount a protective immune memory response to influenza A virus [IAV; Hong Kong/X31 (HKx31), H3N2]. Here, Atm wildtype (WT) and knockout (Atm-null) mice were used to investigate how Atm is required to regenerate the injured airway epithelium following IAV infection. When compared with WT mice, naive Atm-null mice had increased airway resistance and reduced lung compliance that worsened during infection before returning to naïve levels by 56 days postinfection (dpi). Although Atm-null lungs appeared pathologically normal before infection by histology, they developed an abnormal proximal airway epithelium after infection that contained E-cadherin+, Sox2+, and Cyp2f2+ cells lacking secretoglobin family 1 A member 1 (Scgb1a1) protein expression. Patchy and low expression of Scgb1a1 were eventually observed by 56 dpi. Genetic lineage tracing in HKx31-infected mice revealed club cells require Atm to rapidly and efficiently restore Scgb1a1 expression in proximal airways. Since Scgb1a1 is an immunomodulatory protein that protects the lung against a multitude of respiratory challenges, failure to efficiently restore its expression may contribute to the respiratory diseases seen in individuals with ataxia telangiectasia.

Neonatal Hyperoxia Activates Activating Transcription Factor 4 to Stimulate Folate Metabolism and Alveolar Epithelial Type 2 Cell Proliferation.

Oxygen supplementation in preterm infants disrupts alveolar epithelial type 2 (AT2) cell proliferation through poorly understood mechanisms. Here, newborn mice are used to understand how hyperoxia stimulates an early aberrant wave of AT2 cell proliferation that occurs between Postnatal Days (PNDs) 0 and 4. RNA-sequencing analysis of AT2 cells isolated from PND4 mice revealed hyperoxia stimulates expression of mitochondrial-specific methylenetetrahydrofolate dehydrogenase 2 and other genes involved in mitochondrial one-carbon coupled folate metabolism and serine synthesis. The same genes are induced when AT2 cells normally proliferate on PND7 and when they proliferate in response to the mitogen fibroblast growth factor 7. However, hyperoxia selectively stimulated their expression via the stress-responsive activating transcription factor 4 (ATF4). Administration of the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia suppressed ATF4 and thus early AT2 cell proliferation, but it had no effect on normative AT2 cell proliferation seen on PND7. Because ATF4 and methylenetetrahydrofolate dehydrogenase are detected in hyperplastic AT2 cells of preterm infant humans and baboons with bronchopulmonary dysplasia, dampening mitochondrial oxidative stress and ATF4 activation may provide new opportunities for controlling excess AT2 cell proliferation in neonatal lung disease.

Does post-operative radiotherapy improve the treatment outcomes of intracranial hemangiopericytoma? A retrospective study.

BACKGROUND: Intracranial hemangiopericytoma is a rare disease and surgery is the mainstay treatment. Although postoperative adjuvant radiotherapy is often used, there are no reports comparing different radiotherapy techniques. The purpose of this study is to analyze the impact of post-operative radiotherapy and different radiotherapy technique on the results in patients with intracranial hemangiopericytoma (HPC). METHODS: We retrospectively reviewed 66 intracranial HPC patients treated between 1999 and 2019 including 29 with surgery followed by radiotherapy (11 with intensity-modulated radiotherapy (IMRT) and 18 with stereotactic radiosurgery (SRS)) and 37 with surgery alone. Chi-square test was used to compare the clinical characteristic between the groups. The Kaplan-Meier method was used to analyze overall survival (OS) and recurrence-free survival (RFS). Multivariate Cox proportional hazards models were used to examine prognostic factors of survival. We also underwent a matched-pair analysis by using the propensity score method. RESULTS: The crude local control rates were 58.6% in the surgery plus post-operative radiotherapy group (PORT) and 67.6% in the surgery alone group (p = 0.453). In the subgroup analysis of the PORT patients, local controls were 72.7% in the IMRT group and 50% in the SRS group (p = 0.228). The median OS in the PORT and surgery groups were 122 months and 98 months, respectively (p = 0.169). The median RFS was 96 months in the PORT group and 72 months in the surgery alone group (p = 0.714). Regarding radiotherapy technique, the median OS and RFS of the SRS group were not significantly different from those in the IMRT group (p = 0.256, 0.960). The median RFS were 112 and 72 months for pathology grade II and III patients, respectively (p = 0.001). Propensity score matching did not change the observed results. CONCLUSION: In this retrospective analysis, PORT did not improve the local control rates nor the survivals. The local control rates after IMRT and SRS were similar even though the IMRT technique had a much higher biological dose compared with the SRS technique.

Low-dose hyperoxia primes airways for fibrosis in mice after influenza A infection.

It is well known that supplemental oxygen used to treat preterm infants in respiratory distress is associated with permanently disrupting lung development and the host response to influenza A virus (IAV). However, many infants who go home with normally functioning lungs are also at risk for hyperreactivity after a respiratory viral infection. We recently reported a new, low-dose hyperoxia mouse model (40% for 8 days; 40×8) that causes a transient change in lung function that resolves, rendering 40×8 adult animals functionally indistinguishable from room air controls. Here we report that when infected with IAV, 40×8 mice display an early transient activation of TGFß signaling and later airway hyperreactivity associated with peribronchial inflammation (profibrotic macrophages) and fibrosis compared with infected room air controls, suggesting neonatal oxygen induced hidden molecular changes that prime the lung for hyperreactive airways disease. Although searching for potential activators of TGFß signaling, we discovered that thrombospondin-1 (TSP-1) is elevated in naïve 40×8 mice compared with controls and localized to lung megakaryocytes and platelets before and during IAV infection. Elevated TSP-1 was also identified in human autopsy samples of former preterm infants with bronchopulmonary dysplasia. These findings reveal how low doses of oxygen that do not durably change lung function may prime it for hyperreactive airways disease by changing expression of genes, such as TSP-1, thus helping to explain why former preterm infants who have normal lung function are susceptible to airway obstruction and increased morbidity after viral infection.

Middle East Respiratory Syndrome (MERS) Virus-Pathophysiological Axis and the Current Treatment Strategies.

Middle East respiratory syndrome (MERS) is a lethal respiratory disease with its first case reported back in 2012 (Jeddah, Saudi Arabia). It is a novel, single-stranded, positive-sense RNA beta coronavirus (MERS-CoV) that was isolated from a patient who died from a severe respiratory illness. Later, it was found that this patient was infected with MERS. MERS is endemic to countries in the Middle East regions, such as Saudi Arabia, Jordan, Qatar, Oman, Kuwait and the United Arab Emirates. It has been reported that the MERS virus originated from bats and dromedary camels, the natural hosts of MERS-CoV. The transmission of the virus to humans has been thought to be either direct or indirect. Few camel-to-human transmissions were reported earlier. However, the mode of transmission of how the virus affects humans remains unanswered. Moreover, outbreaks in either family-based or hospital-based settings were observed with high mortality rates, especially in individuals who did not receive proper management or those with underlying comorbidities, such as diabetes and renal failure. Since then, there have been numerous reports hypothesising complications in fatal cases of MERS. Over the years, various diagnostic methods, treatment strategies and preventive measures have been strategised in containing the MERS infection. Evidence from multiple sources implicated that no treatment options and vaccines have been developed in specific, for the direct management of MERS-CoV infection. Nevertheless, there are supportive measures outlined in response to symptom-related management. Health authorities should stress more on infection and prevention control measures, to ensure that MERS remains as a low-level threat to public health.

Neonatal hyperoxia impairs adipogenesis of bone marrow-derived mesenchymal stem cells and fat accumulation in adult mice.

Preterm birth is a risk factor for growth failure and development of respiratory disease in children and young adults. Their early exposure to oxygen may contribute to lung disease because adult mice exposed to hyperoxia as neonates display reduced lung function, changes in the host response to respiratory viral infections, and develop pulmonary hypertension and heart failure that shortens their lifespan. Here, we provide new evidence that neonatal hyperoxia also impairs growth by inhibiting fat accumulation. Failure to accumulate fat may reflect a systemic defect in adipogenic potential of stem cells because bone marrow-derived mesenchymal cells (BMSCs) isolated from the mice grew slower and were more oxidized compared to controls. They also displayed reduced capacity to accumulate lipid and differentiate into adipocytes. BMSCs from adult mice exposed to neonatal hyperoxia express lower levels of peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor that drives adipocyte differentiation. The defect in adipogenesis was rescued by expressing PPARγ in these cells. These findings reveal early life exposure to high levels of oxygen may suppresses fat accumulation and impair adipogenic differentiation upstream of PPARγ signaling, thus potentially contributing to growth failure seen in people born preterm.

Image-based diagnosis of residual or recurrent nasopharyngeal carcinoma may be a phantom tumor phenomenon.

ABSTRACT: Some nasopharyngeal carcinoma (NPC) patients may present convincing radiological evidence mimicking residual or recurrent tumor after radiotherapy. However, by means of biopsies and long term follow-up, the radiologically diagnosed residuals/recurrences are not always what they appear to be. We report our experience on this "phantom tumor" phenomenon. This may help to avoid the unnecessary and devastating re-irradiation subsequent to the incorrect diagnosis.In this longitudinal cohort study, we collected 19 patients of image-based diagnosis of residual/recurrent NPC during the period from Feb, 2010 to Nov. 2016, and then observed them until June, 2019. They were subsequently confirmed to have no residual/recurrent lesions by histological or clinical measures. Image findings and pathological features were analyzed.Six patients showed residual tumors after completion of radiotherapy and 13 were radiologically diagnosed to have recurrences based on magnetic resonance imaging (MRI) criteria 6 to 206 months after radiotherapy. There were 3 types of image patterns: extensive recurrent skull base lesions (10/19); a persistent or residual primary lesion (3/19); lesions both in the nasopharynx and skull base (6/19). Fourteen patients had biopsy of the lesions. The histological diagnoses included necrosis/ inflammation in 10 (52.7%), granulation tissue with inflammation in 2, and reactive epithelial cell in 1. Five patients had no pathological proof and were judged to have no real recurrence/residual tumor based on the absence of detectable plasma EB virus DNA and subjective judgment. These 5 patients have remained well after an interval of 38-121 months without anti-cancer treatments.Image-based diagnosis of residual or recurrent nasopharyngeal carcinoma may be unreliable. False positivity, the "phantom tumor phenomenon", is not uncommon in post-radiotherapy MRI. This is particularly true if the images show extensive skull base involvement at 5 years or more after completion of radiotherapy. MRI findings compatible with NPC features must be treated as a real threat until proved otherwise. However, the balance between under- and over-diagnosis must be carefully sought. Without a pathological confirmation, the diagnosis of residual or recurrent NPC must be made taking into account physical examination results, endoscopic findings and Epstein-Barr virus viral load. A subjective medical judgment is needed based on clinical and laboratory data and the unique anatomic complexities of the nasopharynx.

Neonatal hyperoxia inhibits proliferation and survival of atrial cardiomyocytes by suppressing fatty acid synthesis.

Preterm birth increases the risk for pulmonary hypertension and heart failure in adulthood. Oxygen therapy can damage the immature cardiopulmonary system and may be partially responsible for the cardiovascular disease in adults born preterm. We previously showed that exposing newborn mice to hyperoxia causes pulmonary hypertension by 1 year of age that is preceded by a poorly understood loss of pulmonary vein cardiomyocyte proliferation. We now show that hyperoxia also reduces cardiomyocyte proliferation and survival in the left atrium and causes diastolic heart failure by disrupting its filling of the left ventricle. Transcriptomic profiling showed that neonatal hyperoxia permanently suppressed fatty acid synthase (Fasn), stearoyl-CoA desaturase 1 (Scd1), and other fatty acid synthesis genes in the atria of mice, the HL-1 line of mouse atrial cardiomyocytes, and left atrial tissue explanted from human infants. Suppressing Fasn or Scd1 reduced HL-1 cell proliferation and increased cell death, while overexpressing these genes maintained their expansion in hyperoxia, suggesting that oxygen directly inhibits atrial cardiomyocyte proliferation and survival by repressing Fasn and Scd1. Pharmacologic interventions that restore Fasn, Scd1, and other fatty acid synthesis genes in atrial cardiomyocytes may, thus, provide a way of ameliorating the adverse effects of supplemental oxygen on preterm infants.

Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice.

The severity of COVID-19 lung disease is higher in the elderly and people with pre-existing co-morbidities. People who were born preterm may be at greater risk for COVID-19 because their early exposure to oxygen (hyperoxia) at birth increases the severity of respiratory viral infections. Hyperoxia at birth increases the severity of influenza A virus infections in adult mice by reducing the number of alveolar epithelial type 2 (AT2) cells. Since AT2 cells express the SARS-CoV-2 receptors angiotensin converting enzyme (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2), their expression should decline as AT2 cells are depleted by hyperoxia. Instead, ACE2 was detected in airway Club cells and endothelial cells at birth, and then AT2 cells at one year of age. Neonatal hyperoxia stimulated expression of ACE2 in Club cells and in AT2 cells by 2 months of age. It also stimulated expression of TMPRSS2 in the lung. Increased expression of SARS-CoV-2 receptors was blocked by mitoTEMPO, a mitochondrial superoxide scavenger that reduced oxidative stress and DNA damage seen in oxygen-exposed mice. Our finding that hyperoxia enhances the age-dependent expression of SARS-CoV-2 receptors in mice helps explain why COVID-19 lung disease is greater in the elderly and people with pre-existing co-morbidities.

Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice.

The severity of COVID-19 lung disease is higher in the elderly and people with pre-existing co-morbidities. People who were born preterm may be at greater risk for COVID-19 because their early exposure to oxygen at birth increases their risk of being hospitalized when infected with RSV and other respiratory viruses. Our prior studies in mice showed how high levels of oxygen (hyperoxia) between postnatal days 0-4 increases the severity of influenza A virus infections by reducing the number of alveolar epithelial type 2 (AT2) cells. Because AT2 cells express the SARS-CoV-2 receptors angiotensin converting enzyme (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2), we expected their expression would decline as AT2 cells were depleted by hyperoxia. Instead, we made the surprising discovery that expression of Ace2 and Tmprss2 mRNA increases as mice age and is accelerated by exposing mice to neonatal hyperoxia. ACE2 is primarily expressed at birth by airway Club cells and becomes detectable in AT2 cells by one year of life. Neonatal hyperoxia increases ACE2 expression in Club cells and makes it detectable in 2-month-old AT2 cells. This early and increased expression of SARS-CoV-2 receptors was not seen in adult mice who had been administered the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia. Our finding that early life insults such as hyperoxia enhances the age-dependent expression of SARS-CoV-2 receptors in the respiratory epithelium helps explain why COVID-19 lung disease is greater in the elderly and people with pre-existing co-morbidities.

Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis.

The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell-cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+ transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states.

Tumor Necrosis Factor Induces Obliterative Pulmonary Vascular Disease in a Novel Model of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

OBJECTIVE: Connective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) is the second most common etiology of PAH and carries a poor prognosis. Recently, it has been shown that female human tumor necrosis factor (TNF)-transgenic (Tg) mice die of cardiopulmonary disease by 6 months of age. This study was undertaken to characterize this pathophysiology and assess its potential as a novel model of CTD-PAH. METHODS: Histologic analysis was performed on TNF-Tg and wild-type (WT) mice to characterize pulmonary vascular and right ventricular (RV) pathology (n = 40 [4-5 mice per group per time point]). Mice underwent right-sided heart catheterization (n = 29) and micro-computed tomographic angiography (n = 8) to assess vascular disease. Bone marrow chimeric mice (n = 12), and anti-TNF-treated mice versus placebo-treated mice (n = 12), were assessed. RNA sequencing was performed on mouse lung tissue (n = 6). RESULTS: TNF-Tg mice displayed a pulmonary vasculopathy marked by collagen deposition (P < 0.001) and vascular occlusion (P < 0.001) with associated RV hypertrophy (P < 0.001) and severely increased RV systolic pressure (mean ± SD 75.1 ± 19.3 mm Hg versus 26.7 ± 1.7 mm Hg in WT animals; P < 0.0001). TNF-Tg mice had increased α-smooth muscle actin (α-SMA) staining, which corresponded to proliferation and loss of von Willebrand factor (vWF)-positive endothelial cells (P < 0.01). There was an increase in α-SMA-positive, vWF-positive cells (P < 0.01), implicating endothelial-mesenchymal transition. Bone marrow chimera experiments revealed that mesenchymal but not bone marrow-derived cells are necessary to drive this process. Treatment with anti-TNF therapy halted the progression of disease. This pathology closely mimics human CTD-PAH, in which patient lungs demonstrate increased TNF signaling and significant similarities in genomic pathway dysregulation. CONCLUSION: The TNF-Tg mouse represents a novel model of CTD-PAH, recapitulates key disease features, and can serve as a valuable tool for discovery and assessment of therapeutics.

Heart-sparing effect of postmastectomy radiotherapy for breast cancer patients: A dosimetric study of cardiac substructures.

We investigated to what extent can the dose-volumes of the coronary artery and the cardiac substructures be reduced by using IMRT technique in left-sided breast cancer patients. We chose 40 pN2M0 patients treated with postmastectomy IMRT. The original treatment plans were retrieved and the (internal mammary nodes) IMNs and cardiac substructure delineations were added. Three sets of dose-volume parameters including the original plans without internal mammary irradiation (IMNI), the plans with IMNI, and the plans with dose constraints to the heart, were derived. In left-sided patients, when IMNI was included, the V30 for right ventricle (RV), left ventricle (LV), pulmonic valve (PV), and left anterior descending artery (LADA) were 56.37% ± 7.9%, 25.3% ± 7.3%, 48.3% ± 6.3%, and 69.7% ± 6.4%, respectively. Of the 4 main coronary arteries, LADA had the highest dose followed by the left main coronary artery (LMCA). LADA had a V40 of 62% ± 9.7% vs 13.5% ± 3.5%, and a V50 of 27.5% ± 4.7% vs 0, with and without IMNI. For the right-sided patients, the V30s for all the heart substructures were 0 with or without IMNI. When we set a dose constraint of V40 < 10% for the LADA in the left-sided patients, the PTV volumes covered by 50 Gy decreased by only 1%. IMNI increased the V30 of the right and left ventricle and significantly increased the V40 and V50 to the LADA of left-sided breast cancer patients. IMRT markedly reduces the dose to the main coronary arteries and the right and left ventricle.

The biological activities of the spiderworts (Tradescantia).

Widely used throughout the world as traditional medicine for treating a variety of diseases ranging from cancer to microbial infections, members of the Tradescantia genus show promise as sources of desirable bioactive compounds. The bioactivity of several noteworthy species has been well-documented in scientific literature, but with nearly seventy-five species, there remains much to explore in this genus. This review aims to discuss all the bioactivity-related studies of Tradescantia plants and the compounds discovered, including their anticancer, antimicrobial, antioxidant, and antidiabetic activities. Gaps in knowledge will also be identified for future research opportunities.

Pulmonary mechanics and structural lung development after neonatal hyperoxia in mice.

BACKGROUND: Supplemental oxygen exposure administered to premature infants is associated with chronic lung disease and abnormal pulmonary function. This study used mild (40%), moderate (60%), and severe (80%) oxygen to determine how hyperoxia-induced changes in lung structure impact pulmonary mechanics in mice. METHODS: C57BL/6J mice were exposed to room air or hyperoxia from birth through postnatal day 8. Baseline pulmonary function and methacholine challenge was assessed at 4 and 8 weeks of age, accompanied by immunohistochemical assessments of both airway (smooth muscle, tethering) and alveolar (simplification, elastin deposition) structure. RESULTS: Mild/moderate hyperoxia increased baseline airway resistance (40% only) and airway hyperreactivity (40 and 60%) at 4 weeks accompanied by increased airway smooth muscle deposition, which resolved at 8 weeks. Severe hyperoxia increased baseline compliance, baseline resistance, and total elastin/surface area ratio without increasing airway hyperreactivity, and was accompanied by increased alveolar simplification, decreased airway tethering, and changes in elastin distribution at both time points. CONCLUSIONS: Mild to moderate hyperoxia causes changes in airway function and airway hyperreactivity with minimal parenchymal response. Severe hyperoxia drives its functional changes through alveolar simplification, airway tethering, and elastin redistribution. These differential responses can be leveraged to further develop hyperoxia mouse models.