Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells
. Molecular differences in rare individual cells in the initial population ...enable certain cells to become resistant to therapy
; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues.
Liver diseases contribute to ~2 million deaths each year and account for 4% of all deaths globally. Despite various treatment options, the management of liver diseases remains challenging. Physical ...exercise is a promising nonpharmacological approach to maintain and restore homeostasis and effectively prevent and mitigate liver diseases. In this review, we delve into the mechanisms of physical exercise in preventing and treating liver diseases, highlighting its effects on improving insulin sensitivity, regulating lipid homeostasis, and modulating immune function. In addition, we evaluate the impact of physical exercise on various liver diseases, including liver ischemia/reperfusion injury, cardiogenic liver disease, metabolic dysfunction–associated steatotic liver disease, portal hypertension, cirrhosis, and liver cancer. In conclusion, the review underscores the effectiveness of physical exercise as a beneficial intervention in combating liver diseases.
Chorioamnionitis has been linked to spontaneous preterm labor and complications such as neonatal sepsis. We hypothesized that microbial cell-free (cf) DNA would be detectable in maternal plasma in ...patients with chorioamnionitis and could be the basis for a non-invasive method to detect fetal exposure to microorganisms.
The purpose of this study was to determine whether next generation sequencing could detect microbial cfDNA in maternal plasma in patients with chorioamnionitis.
Maternal plasma (n = 94) and umbilical cord plasma (n = 120) were collected during delivery at gestational age 28-41 weeks. cfDNA was extracted and sequenced. Umbilical cord plasma samples with evidence of contamination were excluded. The prevalence of microorganisms previously implicated in choriomanionitis, neonatal sepsis and intra-amniotic infections, as described in the literature, were examined to determine if there was enrichment of these microorganisms in this cohort. Specific microbial cfDNA associated with chorioamnionitis was first detected in umbilical cord plasma and confirmed in the matched maternal plasma samples (n = 77 matched pairs) among 14 cases of histologically confirmed chorioamnionitis and one case of clinical chorioamnionitis; 63 paired samples were used as controls. A correlation of rank of a given microorganism across maternal plasma and matched umbilical cord plasma was used to assess whether signals found in umbilical cord plasma were also present in maternal plasma.
Microbial DNA sequences associated with clinical and/or histological chorioamnionitis were enriched in maternal plasma in cases with suspected chorioamnionitis when compared to controls (12/14 microorganisms, p = 0.02). Analysis of the microbial cfDNA in umbilical cord plasma among the 1,251 microorganisms detectable with this assay identified Streptococcus mitis, Ureaplasma spp., and Mycoplasma spp. in cases of suspected chorioamnionitis. This assay also detected cfDNA from Lactobacillus spp. in controls. Comparison between maternal plasma and umbilical cord plasma confirmed these signatures were also present in maternal plasma. Unbiased analysis of microorganisms with significantly correlated signal between matched maternal plasma and umbilical cord plasma identified the above listed 3 microorganisms, all of which have previously been implicated in patients with chorioamnionitis (Mycoplasma hominis p = 0.0001; Ureaplasma parvum p = 0.002; Streptococcus mitis p = 0.007). These data show that the pathogen signal relevant for chorioamnionitis can be identified in both maternal and umbilical cord plasma.
This is the first report showing the detection of relevant microbial cell-free cfDNA in maternal plasma and umbilical cord plasma in patients with clinical and/or histological chorioamnionitis. These results may lead to the development of a specific assay to detect perinatal infections for targeted therapy to reduce early neonatal sepsis complications.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Sutureless gastroschisis repair offers an alternative to the traditional sutured method and has been associated with decreased intubation time. Published study results are inconsistent ...regarding the advantages of sutureless closure. OBJECTIVE: To compare the clinical outcomes of sutureless and sutured gastroschisis repair. DESIGN, SETTING, AND PARTICIPANTS: A single-center cohort review was performed of all consecutive patients (n = 97) who underwent gastroschisis repair from February 1, 2007, to April 30, 2017, at the University of California, San Francisco. Patients’ medical records were evaluated for clinical characteristics and outcomes. Cases with incomplete data during initial hospitalization were excluded. MAIN OUTCOMES AND MEASURES: Length of hospital stay, time to full enteral feeds, total parenteral nutrition duration, days requiring intravenous analgesia, days intubated, wound infection rate, antibiotic treatment duration, rate of umbilical hernias that required an operation, and readmission rate. RESULTS: In total, 97 patients (47 48% were female and 50 52% were male with a mean SD age of 2.8 2.8 days) underwent gastroschisis repair, of which 7 were excluded for incomplete medical record. Of the 90 patients included in the study, 50 (56%) underwent sutured closure and 40 (44%) underwent sutureless closure. No statistical difference was found between the sutured and sutureless groups in length of hospital stay (mean SD days, 43.9 40.4 vs 36.7 21.2; P = .71), time to full enteral feeds (mean SD days, 31.4 20.2 vs 27.9 17.3; P = .22), total parenteral nutrition duration (mean SD days, 33.5 29.8 vs 27.4 18.2; P = .23), wound infection rates (14 28% vs 10 25%; P = .81), and readmission rates (5 10% vs 7 18%; P = .36). The sutureless group, compared with the sutured group, had substantially fewer days receiving antibiotics (mean SD, 7.2 6.4 vs 12.4 13.2; P = .003), fewer days intubated (mean SD, 2.8 3.3 vs 6.8 1.3; P = .001), fewer days receiving intravenous analgesia (mean SD, 4.2 4.0 vs 7.1 4.5; P = .003), and fewer patients that required silo reduction (25 63% vs 48 96%; P < .001). Sutureless closures, compared with the sutured technique, had considerably more umbilical hernias requiring surgical repair (5 13% vs 0; P = .02). CONCLUSIONS AND RELEVANCE: Sutureless repair of gastroschisis appears to be associated with a statistically significant reduction in mechanical ventilation duration and pain medication requirements but may increase umbilical hernia risk. Multicenter randomized clinical trials are necessary to determine the true advantages of the sutureless approach.
The treatment of malignant melanoma has drastically changed over the past decade with the advent of immune checkpoint blockade, targeted therapy with BRAF/MEK inhibition, and other novel therapies ...such as oncolytic virus intralesional therapy. Despite improvements in patient response rates and survival with these new treatments, there exists a large portion of patients with surgically resectable disease that are high risk for relapse. Patients with high-risk resectable melanoma account for up to 20% of newly diagnosed cases. For this high-risk group of patients, neoadjuvant therapy has many purposed advantages over adjuvant therapy, including a more robust immune response due to abundant tumor antigens at treatment initiation, the ability to assess pathologic response to therapy, tumor downstaging leading to increased disease resectability, and a potential decreased need for extensive lymphadenectomies. These findings have been backed by preclinical models and multiple neoadjuvant trials are underway. In this review, we will discuss the trials that have set the foundation for the current treatment standards and discuss the role and rationale for neoadjuvant therapy for high-risk malignant melanomas.
Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are ...needed
. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts
of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy.
Background
Regional lymph node metastasis in extremity and trunk soft tissue sarcoma (ETSTS) is rare with no standardized management. We sought to determine management patterns for regional lymph ...node metastasis in ETSTS.
Methods
A survey regarding the management of ETSTS lymph node metastasis was distributed to the membership of the Musculoskeletal Tumor Society (MSTS) and the Society of Surgical Oncology (SSO) in January 2022. The survey queried the type of training (surgical oncology, orthopedic oncology), details of their practice setting, and management decisions of hypothetical ETSTS scenarios that involved potential or confirmed lymph node metastasis.
Results
The survey was distributed to 349 MSTS members (open rate of 63%, completion rate 21%) and 3026 SSO members (open rate of 55%, completion rate 4.7%) and was completed by 214 respondents, of whom 73 (34.1%) and 141 (65.9%) were orthopedic oncology and surgical oncology fellowship-trained, respectively. The majority of respondents practiced in an academic setting (
n
= 171, 79.9%) and treat >10 extremity sarcoma cases annually (
n
= 138, 62.2%). In scenarios with confirmed nodal disease for clear cell and epithelioid sarcoma, surgical oncologists were inclined to perform lymphadenectomy, while orthopedic oncologists were inclined to offer targeted lymph node excision with adjuvant radiation (
p
< 0.001). There was heterogeneity of responses regarding the management of nodal disease regardless of training background.
Conclusion
Self-reported management of nodal disease in ETSTS was variable among respondent groups with differences and similarities based on training background. These data highlight the variability of practice for nodal disease management and the need for consensus-based guidelines.
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