Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response to treatment remains unclear. ...Here we found that a soft extracellular matrix empowers redox homeostasis. Cells cultured on a soft extracellular matrix display increased peri-mitochondrial F-actin, promoted by Spire1C and Arp2/3 nucleation factors, and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in mitochondrial dynamics lead to increased production of mitochondrial reactive oxygen species and activate the NRF2 antioxidant transcriptional response, including increased cystine uptake and glutathione metabolism. This retrograde response endows cells with resistance to oxidative stress and reactive oxygen species-dependent chemotherapy drugs. This is relevant in a mouse model of metastatic breast cancer cells dormant in the lung soft tissue, where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented disseminated cancer-cell awakening. We propose that targeting this mitochondrial dynamics- and redox-based mechanotransduction pathway could open avenues to prevent metastatic relapse.
It is not fully understood why COVID-19 is typically milder in children
. Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed ...paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.
Background
Despite a number of studies comparing laparoscopic inguinal hernia repair (LH) and open herniorrhaphy (OH), the putative advantage of LH remains controversial due to a paucity of firm ...evidence. We hypothesized that LH has both advantages and disadvantages compared to OH and sought to clarify them by comprehensively analyzing the retrospective data using the combination of multiple statistical methods.
Methods
Operative data for inguinal hernia during the period from February 1999 to December 2019 were examined. The patients were assigned into two groups according to the surgical procedure: laparoscopic percutaneous extraperitoneal closure (LPEC,
n
= 2410) and OH (
n
= 2038). Operative and anesthesia times and incidence of postoperative complications were evaluated using the propensity score methods and log-rank test.
Results
In comparison with OH, operative time of LPEC was longer for unilateral repair (21.59 ± 8.1 min vs 18.01 ± 8.0 min;
p
< 0.001) and shorter for bilateral repairs (28.55 ± 10.1 min vs 33.23 ± 11.7 min;
p
< 0.001), while anesthesia times were longer for both unilateral repair (57.67 ± 10.1 min vs 40.62 ± 11.9 min;
p
< 0.001) and bilateral repairs (65.95 ± 12.5 min vs 56.35 ± 15.1 min;
p
< 0.001). LPEC significantly reduced the risk of metachronous contralateral hernia (MCLH) (0.52% vs 9.29%;
p
< 0.001), but the recurrence rate was higher (0.21% vs 0.04%;
p
= 0.002) than OH. Orchiectomy due to testicular atrophy or torsion was required in 3 cases of OH (0.19%), whereas it was not seen in LPEC.
Conclusions
LPEC had a less risk of MCLH and testicular complications but was associated with a higher recurrence rate and longer anesthesia time. Propensity scoring techniques can enhance the robustness of retrospective comparisons between groups over several years of data collection, which is frequently required in pediatric surgery studies.
Background
CDH UK is a registered charity governed by a volunteer committee and providing informal support to patients, families and healthcare workers affected directly or indirectly with congenital ...diaphragmatic hernia (CDH) internationally. This is the first patient-led survey undertaken by CDH UK aiming for highlighting the feeding problems and their impact on the daily life of CDH survivors.
Methods
Answers from CDH survivors were collected through an online questionnaire (SurveyMonkey
®
) undertaken by CDH UK. The questionnaire contained questions about their feeding problems and support they were receiving for it.
Main results
Overall, 151 patients answered some parts of the survey and 102 patients completed the questionnaire. Overall, 116 (76.8%) responders reported suffering from any type of feeding issue. Gastric acid reflux (GER) and growth retardation were the commonest symptoms experienced by 97 (91.5%) and 72 (62.2%) responders, respectively. Only 18 (17.0%) responders have received any written information on feeding or details of patient/parent support. Eighty (75.5%) responders are satisfied with the level of support they are receiving, but 78 (76.4%) answered that the whole experience associated with the disease has been very or extremely stressful.
Conclusions
CDH survivors frequently have various issues with feeding, which may not be adequately supported or discussed clinically. It is desirable to assist the patients to reliable resources of long-term support, including multidisciplinary team (MDT) approach.
Three-dimensional hydrogel-based organ-like cultures can be applied to study development, regeneration, and disease in vitro. However, the control of engineered hydrogel composition, mechanical ...properties and geometrical constraints tends to be restricted to the initial time of fabrication. Modulation of hydrogel characteristics over time and according to culture evolution is often not possible. Here, we overcome these limitations by developing a hydrogel-in-hydrogel live bioprinting approach that enables the dynamic fabrication of instructive hydrogel elements within pre-existing hydrogel-based organ-like cultures. This can be achieved by crosslinking photosensitive hydrogels via two-photon absorption at any time during culture. We show that instructive hydrogels guide neural axon directionality in growing organotypic spinal cords, and that hydrogel geometry and mechanical properties control differential cell migration in developing cancer organoids. Finally, we show that hydrogel constraints promote cell polarity in liver organoids, guide small intestinal organoid morphogenesis and control lung tip bifurcation according to the hydrogel composition and shape.
Purpose
This paper aims to build upon previous work to definitively establish in vitro models of murine pseudoglandular stage lung development. These can be easily translated to human fetal lung ...samples to allow the investigation of lung development in physiologic and pathologic conditions.
Methods
Lungs were harvested from mouse embryos at E12.5 and cultured in three different settings, i.e., whole lung culture, mesenchyme-free epithelium culture, and organoid culture. For the whole lung culture, extracted lungs were embedded in Matrigel and incubated on permeable filters. Separately, distal epithelial tips were isolated by firstly removing mesothelial and mesenchymal cells, and then severing the tips from the airway tubes. These were then cultured either in branch-promoting or self-renewing conditions.
Results
Cultured whole lungs underwent branching morphogenesis similarly to native lungs. Real-time qPCR analysis demonstrated expression of key genes essential for lung bud formation. The culture condition for epithelial tips was optimized by testing different concentrations of FGF10 and CHIR99021 and evaluating branching formation. The epithelial rudiments in self-renewing conditions formed spherical 3D structures with homogeneous Sox9 expression.
Conclusion
We report efficient protocols for ex vivo culture systems of pseudoglandular stage mouse embryonic lungs. These models can be applied to human samples and could be useful to paediatric surgeons to investigate normal lung development, understand the pathogenesis of congenital lung diseases, and explore novel therapeutic strategies.
Laparoscopic percutaneous extraperitoneal closure (LPEC) has become a common procedure for repairing inguinal hernia. As a laparoscopic approach, pediatric surgical trainees require more training to ...learn LPEC than a traditional open approach. This study aimed to clarify the experience needed to acquire the skill to perform LPEC adequately.
This descriptive single-center study used clinical data from patients who underwent LPEC between May 2009 and May 2016. The mean operative time for ten consecutive unilateral repairs was used as an index of proficiency with the procedure. The number of repairs performed before the mean operative time became less than 20 min was evaluated for each trainee.
During the study period, six pediatric surgical trainees participated in the training independently. The number of the patients was 987. The total number of repairs was 1436, including 538 unilateral repairs and 449 concurrent bilateral repairs. Overall, the mean operative time was 21.8 ± 8.1 min for unilateral repair and 31.4 ± 9.7 min for concurrent bilateral repairs. The mean number of repairs performed before the acquisition of skill for dexterous LPEC was 125.1 ± 29.5.
Although there were individual differences, all trainees acquired the skill to perform LPEC adequately within one year. With appropriate guidance, LPEC can become a standard technique for pediatric surgical trainees, along with traditional open surgery. These results provide valuable information for planning LPEC training.
What is currently known about this topic?•Surgeons encounter various anatomical aberrations in lung lobectomy, e.g., atypical branches of pulmonary vessels and incomplete fissures. Although the ...prevalence of anatomical variation has been well reported in adults, few reports exist in children with congenital lung malformations.What new information is contained in this article?•Anatomical variations were similarly observed in children with congenital lung malformations as adults. The degree of incomplete fissure was associated with prolonged operative times, but there were no other variations that significantly affect surgical complexity of thoracic lobectomy in children.
: Sufficient knowledge of anatomy including normal patterns and aberrant variations is crucial in thoracoscopic lobectomy for congenital lung malformations (CLMs). This study aimed to investigate the prevalence of anatomical variations and their correlations with surgical outcome.
: Video-recordings of thoracoscopic lobectomy performed for CLMs between 2009 and 2021 were reviewed. The incidences of surgically relevant variations, including abnormal branches of pulmonary arteries and veins, aberrant systemic arteries, and incomplete fissures (as classified by Craig) were assessed in comparison with the previously published reports. Moreover, multiple univariate analyses were performed to seek correlations between surgical finding and prolonged operative times and postoperative drainage.
: Fifty-six lobectomies were reviewed. Variations of pulmonary arteries were more commonly seen in the left lung (29.6%) compared to right (10.7%). The prevalence of atypical pulmonary venous branches was similar between the right (13.8%) and left (18.5%). The right upper oblique fissure was frequently associated with Grade 2 incomplete fissure (44.8%). Grade 3 incomplete fissure was rare (3.4%) in the right lower oblique fissure but relatively common (14.3 – 18.5%) in other locations. Grade 4 incomplete fissure was limited to the right horizontal fissure (1.7%). Multiple univariate analyses demonstrated a significant correlation between any degree of incomplete fissure and prolonged operative time (p < 0.05), whereas no factor was identified to affect need for postoperative drainage.
: The incidence of anatomical variations in CLM patients was similar to that reported in adults. Review of intra-operative video footage was useful to closely evaluate and understand anatomical variations.
Anorectal malformations (ARM) represent a broad spectrum of patients with different level of the rectum and type of a fistula. Standardized approaches are usually successful, but patients ...occasionally present with an unusual course of fistula which requires a modified surgical strategy. We present here three male ARM patients with an atypical fistula which did not have connection with the urinary tract, but ran near the fistula. Case 1 has a low-type ARM with a rectoscrotal fistula running deep and partly involved in the corpus spongiosum. Anorectoplasty was performed through an anterior sagittal incision and the anterior wall of the fistula was laid open leaving the posterior wall undetached. Case 2 was diagnosed with an intermediate-type ARM with a long rectoscrotal fistula running near and parallel the urethra. Posterior sagittal anorectoplasty (PSARP) was performed leaving the fistula untouched. Case 3 presented with an intermediate-type ARM with a rectoperineal fistula adherent to the urethra. The patient was treated by PSARP leaving the fistula and part of the muscle coat of the rectum in situ. All the cases were smoothly discharged and no urological complication nor problem associated with the residual fistula was observed at the latest follow-up (17 months–2 years). Preoperative distal colostography with the aid of diverting colostomy was importantly useful for deciding surgical procedure.
Purpose
Laparoscopic percutaneous extraperitoneal closure (LPEC) has become routine for repairing pediatric inguinal hernia (IH). Reports on the effective repair of IH in challenging cases, such as ...extremely low birth weight infants (ELBWI) who become symptomatic soon after birth and have surgery before 1 year of age, are rare; and conventional herniotomy (CH) in ELBWI requires extensive experience of neonatal surgery. We compared LPEC with CH for treating ELBWI with IH.
Methods
Consecutive ELBWI with IH treated by either LPEC (
n
= 17) or CH (
n
= 22) before 1 year of age between 2012 and 2017 were reviewed. LPEC were performed by consultant pediatric surgeons (CPS;
n
= 3) with experience of at least 200 cases each. In CH, 11 cases were treated by CPS and 11 by CPS-supervised surgical trainees.
Results
There were no intraoperative complications. Operative time and anesthesia time for bilateral IH repairs were both shorter in LPEC. Postoperative sequelae were recurrence (LPEC;
n
= 1; repaired by redo LPEC 2 months after the initial repair) and intravenous rehydration (CH;
n
= 1; for persistent post-anesthetic vomiting). Recovery was unremarkable in all cases without additional analgesia.
Conclusion
LPEC would appear to be a viable option for treating IH in ELBWI, especially bilateral cases.
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