Neoadjuvant therapy is recommended for locally advanced esophageal cancer, but the optimal strategy remains unclear. We aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy ...(nCRT) versus neoadjuvant chemotherapy (nCT) followed by minimally invasive esophagectomy (MIE) for locally advanced esophageal squamous cell carcinoma (ESCC).
Eligible patients staged as cT3-4aN0-1M0 ESCC were randomly assigned (1 : 1) to the nCRT or nCT group stratified by age, cN stage, and centers. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while concurrent radiotherapy was added for the nCRT group; then MIE was carried out. The primary endpoint was 3-year overall survival. This study is registered with ClinicalTrials.gov (NCT03001596).
A total of 264 patients were eligible for the intention-to-treat analysis. By 30 November 2021, 121 deaths had occurred. The median follow-up was 43.9 months (interquartile range 36.6-49.3 months). The overall survival in the intention-to-treat population was comparable between the nCRT and nCT strategies hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.58-1.18; P = 0.28, with a 3-year survival rate of 64.1% (95% CI 56.4% to 72.9%) versus 54.9% (95% CI 47.0% to 64.2%), respectively. There were also no differences in progression-free survival (HR 0.83, 95% CI 0.59-1.16; P = 0.27) and recurrence-free survival (HR 1.07, 95% CI 0.71-1.60; P = 0.75), although the pathological complete response in the nCRT group (31/112, 27.7%) was significantly higher than that in the nCT group (3/104, 2.9%; P < 0.001). Besides, a trend of lower risk of recurrence was observed in the nCRT group (P = 0.063), while the recurrence pattern was similar (P = 0.802).
NCRT followed by MIE was not associated with significantly better overall survival than nCT among patients with cT3-4aN0-1M0 ESCC. The results underscore the pending issue of the best strategy of neoadjuvant therapy for locally advanced bulky ESCC.
•The CMISG1701 trial assessed the safety and efficacy of nCRT versus nCT followed by MIE for locally advanced bulky ESCC.•The nCRT followed by MIE strategy could not improve survival significantly compared with the nCT strategy.•The best strategy of neoadjuvant therapy for locally advanced bulky ESCC remains a pending issue.
Seven different conversion coatings (which can be classified into three types: MgP, ZnP and CaP) were prepared on Mg alloy substrates to compare the corrosion resistance and biocompatibility of these ...coatings. Biocompatibility and cytotoxicity of different coated samples and bare Mg alloy were studied using the CCK-8 test. The corrosion resistance of different conversion coatings was comparatively studied by electrochemical tests (OCP, EIS and PDP) and long-term immersion test in Hanks' solution. Based on the experimental results, the corrosion mechanism of different types of conversion coatings and Mg alloy substrate was proposed and investigated.
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•In this work, seven kinds of conversion coatings (which can be classified into three types of MgP, ZnP and CaP) were prepared by changing the content of Mg2+, Zn2+ and Ca2+ ions in conversion solutions.•The conversion coating generation priority was proposed: ZnP type > CaP type > MgP type.•The anti-corrosion performance of different coated samples are systematically investigated in Hanks' solution, and corrosion mechanisms different coatings are proposed from the perspective of filiform and pitting corrosion.•The biocompatibility and biodegradability of different conversion coatings and bare Mg alloy were investigated.•A “time constant shielding (TCS)” effect was proposed to explain the interaction between conductive loops and inductive loops in the EIS plot.
Photovoltaic modules subjected to partial shading conditions (PSC) can drastically decrease their power output. Hence, there have been various maximum power point tracking (MPPT) control algorithms ...developed to reduce or counteract the shading effects. Recently, a new metaheuristic algorithm known as firefly algorithm (FA) was developed, which, under PSC, has been shown to successfully track the global maximum point (GMP). Nevertheless, the FA still has some inherent problems that may hinder the performance of the MPPT. This paper modifies the existing FA to counteract these problems. As will be demonstrated in this paper, the proposed modified FA method can reduce the number of computation operations and the time for converging to the GMP that the existing FA requires. Experimental results show that the proposed method can track the global point under various PSC, has a faster convergence time compared with the FA, and can effectively suppress power and voltage fluctuations.
Abstract Background The chronic shortage of kidneys for transplantation has increased the number of living donations, but demand remains high, which has created a long waiting list of end-stage ...kidney disease patients. Donors with decreased renal mass may suffer a higher risk of developing proteinuria, hypertension (HTN), and chronic renal disease (CKD) during long-term follow-up. Methods We retrospectively retrieved medical data of living kidney donors at our hospital over the past 28 years. Results There were 45 male and 60 female donors with a mean donation age of 46.34 ± 12.47 years (range = 20–70y). The mean follow-up duration was 4.67 ± 4.78 years. The serum creatinine (Cr) at donation was 0.93 ± 0.22 mg/dL, while the latest Cr was 1.26 ± 0.45 mg/dL ( P < .001). The mean age at follow-up was 50.95 ± 14.57 years. At last follow-up, eight subjects (7.6%) displayed HTN requiring treatment, 10 (9.5%), proteinuria and 55.4%, an estimated glomerular filtration rate (eGFR) of less than 60 mL/min, including one with diabetic nephropathy at 10 years after donation who required long-term hemodialysis. Although gender did not correlate with occurrence of HTN, proteinuria, and CKD, the occurrence of CKD was associated with age at donation ( P < .001, odds ratio OR = 1.076), and age at follow-up ( P < .001, OR = 1.071). HTN donors were older ( P = .036, OR = 1.057) with longer follow-up durations ( P = .007, OR = 1.166) and had higher Cr values at donation ( P = .044, OR = 94.4). Donors with proteinuria were not related to gender, follow-up duration, initial Cr, warm ischemic time, or duration of admission. eGFR was indeed worse after donation ( P = .002). Conclusions Our results indicated a significant proportion of living donors may develop CKD upon long-term follow-up. The factors affecting donor risk of CKD were baseline renal function, older age, and duration after kidney donation.
Abstract
STUDY QUESTION
What is the transcriptome signature associated with poor performance of rescue IVM (rIVM) oocytes and how can we rejuvenate them?
SUMMARY ANSWER
The GATA-1/CREB1/WNT ...signalling axis was repressed in rIVM oocytes, particularly those of poor quality; restoration of this axis may produce more usable rIVM oocytes.
WHAT IS KNOWN ALREADY
rIVM aims to produce mature oocytes (MII) for IVF through IVM of immature oocytes collected from stimulated ovaries. It is not popular due to limited success rate in infertility treatment. Genetic aberrations, cellular stress and the absence of cumulus cell support in oocytes could account for the failure of rIVM.
STUDY DESIGN, SIZE, DURATION
We applied single-cell RNA sequencing (scRNA-seq) to capture the transcriptomes of human in vivo oocytes (IVO) (n = 10) from 7 donors and rIVM oocytes (n = 10) from 10 donors. The effects of maternal age and ovarian responses on rIVM oocyte transcriptomes were also studied. In parallel, we studied the effect of gallic acid on the maturation rate of mouse oocytes cultured in IVM medium with (n = 84) and without (n = 85) gallic acid.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Human oocytes were collected from donors aged 28–41 years with a body mass index of <30. RNA extraction, cDNA generation, library construction and sequencing were performed in one preparation. scRNA-seq data were then processed and analysed. Selected genes in the rIVM versus IVO comparison were validated by quantitative real-time PCR. For the gallic acid study, we collected immature oocytes from 5-month-old mice and studied the effect of 10-μM gallic acid on their maturation rate.
MAIN RESULTS AND THE ROLE OF CHANCE
The transcriptome profiles of rIVM/IVO oocytes showed distinctive differences. A total of 1559 differentially expressed genes (DEGs, genes with at least 2-fold change and adjusted P < 0.05) were found to be enriched in metabolic processes, biosynthesis and oxidative phosphorylation. Among these DEGs, we identified a repression of WNT/β-catenin signalling in rIVM when compared with IVO oocytes. We found that oestradiol levels exhibited a significant age-independent correlation with the IVO mature oocyte ratio (MII ratio) for each donor. rIVM oocytes from women with a high MII ratio were found to have over-represented cellular processes such as anti-apoptosis. To further identify targets that contribute to the poor clinical outcomes of rIVM, we compared oocytes collected from young donors with a high MII ratio with oocytes from donors of advanced maternal age and lower MII ratio, and revealed that CREB1 is an important regulator. Thus, our study identified that GATA-1/CREB1/WNT signalling was repressed in both rIVM oocytes versus IVO oocytes and in rIVM oocytes of lower versus higher quality. Consequently we investigated gallic acid, as a potential antioxidant substrate in human rIVM medium, and found that it increased the mouse oocyte maturation rate by 31.1%.
LARGE SCALE DATA
Raw data from this study can be accessed through GSE158539.
LIMITATIONS, REASONS FOR CAUTION
In the rIVM oocytes of the high- and low-quality comparison, the number of samples was limited after data filtering with stringent selection criteria. For the oocyte stage identification, we were unable to predict the presence of oocyte spindle, so polar body extrusion was the only indicator.
WIDER IMPLICATIONS OF THE FINDINGS
This study showed that GATA-1/CREB1/WNT signalling was repressed in rIVM oocytes compared with IVO oocytes and was further downregulated in low-quality rIVM oocytes, providing us the foundation of subsequent follow-up research on human oocytes and raising safety concerns about the clinical use of rescued oocytes.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the Collaborative Research Fund, Research Grants Council, C4054-16G, and Research Committee Funding (Research Sustainability of Major RGC Funding Schemes), The Chinese University of Hong Kong. The authors have no conflicts of interest to declare.
Abstract Human polyomaviruses (PV), including JC and BK virus, have been reported to cause polyomavirus-associated nephropathy (PVAN), in renal transplant patients. PV infection has been demonstrated ...to be associated with malignancies in animals; however, the association between malignancy and viral infections in humans is not clear. We retrospectively reviewed our 864 (M:F = 502:362) kidney transplant patients over the past 25 years. We identified PVAN in 6 patients (0.69%), including BK nephropathy ( n = 5) and JC nephropathy ( n = 1). Three patients (50%) improved after reducing the immunosuppression, but 3 (50%) progressed to graft loss despite this reduction. Malignancy occurred in 5 out of the 6 patients (83%; P < .0001 compared with patients without PVAN), including transitional cell carcinoma ( n = 2), renal cell carcinoma ( n = 1), squamous cell carcinoma of skin ( n = 1) and Kaposi sarcoma ( n = 1). We concluded that kidney transplant patients with PVAN are at a significantly greater risk to develop malignancy. Whether this is due to a direct effect of PV infection or the result of overimmunosuppression remains to be determined in a future study.
: Background. Tuberculosis (TB) is one of the major causes of morbidity and mortality worldwide. Post‐transplant (post‐Tx) TB is a problem in successful long‐term outcome of renal transplantation ...recipients. It is a life‐threatening opportunistic infection that is frequently encountered, but the diagnosis is often delayed. With the emergence of newer potent immunosuppressive regimens and an increased incidence of TB in the general population, post‐Tx TB among transplant recipients can be anticipated. Our objective was to describe the pattern and risk factors of TB infection, and the prognosis in an endemic area.
Methods. This study was a retrospective review of the records of 756 renal transplant recipients in our hospital during the period from January 1983 to December 2003. The demographic data, transplant characteristics, clinical manifestations, diagnostic criteria, treatment protocol, and long‐term outcome of this cohort of patients were analyzed.
Results. Thirty‐one episodes developed into TB in 29 patients (3.8%) with a mean age of 45.5 (range: 24.2–66.2) years and a mean post‐Tx period of 57.9 (range: 1.2–145.2) months. The forms of the diseases were pulmonary in 22/31 (71%), disseminated in 1/31 (3%), miliary in 1/31 (3%), and extrapulmonary in 7/31 (23%). All patients initially received 4‐drug combination therapy, and then dosage was adjusted based on clinical condition. Because of drug interaction, a mean 2‐fold increase in the dose of calcineurium inhibitor, but no change in steroid, was required. Twenty‐two patients (71%) had an elevated creatinine (Cr) level, and 6 (19%) patients did not recover owing to tissue‐proof acute rejection (3 cases) and chronic allograft nephropathy (3 cases), respectively, after treatment. The serum Cr level on diagnosis of TB was 1.9±0.7 mg/dL; it then deteriorated to 2.4±1.5 mg/dL (P=0.134). Hepatotoxicity developed in 11 patients (35.5%) during treatment. Twenty‐five patients were successfully treated, 2 patients remain under treatment, and 4 (12.9%) died. Based on univariate analysis, we found the post‐Tx TB risk factors were diabetes and more than 3 episodes of rejection, modalities for acute rejection (high‐dose steroid and anti‐lymphocyte globulin), and maintenance therapy with steroid.
Conclusion. Post‐Tx TB is a serious problem worldwide, and a high index of suspicion is warranted to ensure early diagnosis and prompt initiation of treatment for TB among renal transplant patients. The use of optimal immunosuppressive agents to minimize acute rejection seems reasonable to prevent TB infection in endemic areas like Taiwan. More than 9 months of treatment may be necessary to prevent recurrence.
By virtue of its high corrosion resistance and desirable mechanical properties, Mg-based bulk metallic glass (BMG) is a promising candidate material for the biodegradable implants. To investigate the ...impact of microalloying element Ga on the glass-forming ability (GFA) and its effect on the mechanical properties and corrosion behaviors of Mg–Zn–Ca BMG, a series alloys of (Mg66Zn30Ca4)100-xGax (x = 0, 0.25, 0.5, 0.75, 1.0 and 1.25) were synthesized and investigated in this study. According to the XRD results and SEM (backscattered electron) images, the critical diameter (Dc) of Mg66Zn30Ca4 BMG is about 3.5 mm, and 1.0 at.% Ga addition improves the Dc to about 5 mm. Meanwhile, the 1.0 at.% Ga addition improves the fracture strength of Mg–Zn–Ca BMG from 651 MPa to 752 MPa. The corrosion behavior and mechanism of different metallic glass samples were investigated. According to the results of electrochemical tests and immersion test, the addition of Ga can help to form the passive film on the metallic glass substrate and improve its corrosion resistance. Besides, the relationship between the alloy composition and glass-forming ability (GFA) was postulated and interpreted by the theory of binary alloy phase diagrams.
•Mg–Zn–Ca bulk metallic glasses with different content of Ga are prepared successfully.•Corrosion behavior and mechanical properties of different Mg–Zn–Ca-Ga bulk metallic glasses are investigated.•The relationship between glass-forming ability (GFA) and alloy phase diagrams is interpreted.
Mitogen-activated protein kinase (MAPK) pathway plays a major role in pediatric low-grade gliomas (pLGGs). Immunohistochemistry with mutant-specific antibody, VE1, has appeared to be the most ...affordable and rapidly deployable method to identify tumors with aberrant MAPK signaling pathway, by highlighting tumor with
BRAF
V600E
mutation. Nonetheless, positive staining cases but not associated with
BRAF
V600E
mutation are also seen. We analyzed 62 pLGGs for the two commonest genetic aberrations in MAPK pathway:
KIAA1549
-
BRAF
fusion, using reverse-transcriptase polymerase chain reaction, and
BRAF
V600E
mutation, using VE1 antibody and Sanger sequencing. We recorded a specificity and accuracy rate of 68.75% and 75%, respectively, for VE1, when strong cytoplasmic staining is observed. Interestingly, we observed that cells with ganglionic features frequently bind VE1 but not associated with
BRAF
V600E
mutation. Such observation was also confirmed in four cases of differentiating neuroblastoma. This false positive staining may serve as an important confounder in the interpretation of VE1 immunoreactivity with major therapeutic implication. It is important to confirm the presence of
BRAF
V600E
mutation by DNA-based method, especially in tumor entities not known to, or rarely harbor such mutations.
