The First Case of Ischemia-Free Kidney Transplantation in Humans

Background: Ischemia-reperfusion injury (IRI) has been considered an inevitable event in organ transplantation since the first successful kidney transplant was performed in 1954. To avoid IRI, we have established a novel procedure called ischemia-free organ transplantation. Here, we describe the first case of ischemia-free kidney transplantation (IFKT). Materials and Methods: The kidney graft was donated by a 19-year-old brain-dead donor. The recipient was a 47-year-old man with end-stage diabetic nephropathy. The graft was procured, preserved, and implanted without cessation of blood supply using normothermic machine perfusion. Results: The graft appearance, perfusion flow, and urine production suggested that the kidney was functioning well-during the whole procedure. The creatinine dropped rapidly to normal range within 3 days post-transplantation. The levels of serum renal injury markers were low post-transplantation. No rejection or vascular or infectious complications occurred. The patient had an uneventful recovery. Conclusion: This paper marks the first case of IFKT in humans. This innovation may offer a unique solution to optimizing transplant outcomes in kidney transplantation

Fully transformer-based biomarker prediction from colorectal cancer histology: a large-scale multicentric study

Background: Deep learning (DL) can extract predictive and prognostic biomarkers from routine pathology slides in colorectal cancer. For example, a DL test for the diagnosis of microsatellite instability (MSI) in CRC has been approved in 2022. Current approaches rely on convolutional neural networks (CNNs). Transformer networks are outperforming CNNs and are replacing them in many applications, but have not been used for biomarker prediction in cancer at a large scale. In addition, most DL approaches have been trained on small patient cohorts, which limits their clinical utility. Methods: In this study, we developed a new fully transformer-based pipeline for end-to-end biomarker prediction from pathology slides. We combine a pre-trained transformer encoder and a transformer network for patch aggregation, capable of yielding single and multi-target prediction at patient level. We train our pipeline on over 9,000 patients from 10 colorectal cancer cohorts. Results: A fully transformer-based approach massively improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training on a large multicenter cohort, we achieve a sensitivity of 0.97 with a negative predictive value of 0.99 for MSI prediction on surgical resection specimens. We demonstrate for the first time that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem. Interpretation: A fully transformer-based end-to-end pipeline trained on thousands of pathology slides yields clinical-grade performance for biomarker prediction on surgical resections and biopsies. Our new methods are freely available under an open source license

Cultural Inheritance and Innovation—Taking the Heilongjiang Garden Design of the Garden Expo as an Example

With the rapid development of social science and technology civilization, and the acceleration of urbanization, the requirements of urban landscape planning and design are also paying more and more attention to the design concept of “adopting measures to local conditions and putting people first”. Therefore, the inheritance and innovation of urban landscape planning and design based on the culture that can represent local characteristics is a respect for and inheritance of traditional regional culture, the integration of traditional culture and the culture of the new era, and the inevitable trend of modern landscape planning and development. This essay uses the Heilongjiang Garden Engineering Design Project of the Garden Expo as a case to carry out the regional landscape planning and design, inheriting the regional characteristics, and proposing the design concept of “nature and culture growing on black soil”, integrating the characteristics of white mountains and black water into the garden, and seeing the big from the small Interpret the characteristic landscape impression of Heilongjiang and provide a reference for the design of the exhibition garden project in the future

Magnetism of two-dimensional chromium tellurides

2D ferromagnets have garnered considerable attention for their potential applications in spintronics, magnonics, and spin-orbitronics. Chromium tellurides (CrxTey), in particular, have drawn interest due to their exceptional magnetic properties and diverse range of chemical stoichiometries, attributed to the phenomenon of chromium self-intercalation. To provide an in-depth understanding of this complex material class, this review first explains the origin of 2D magnetism using two well-known 2D ferromagnets, CrI3 and Fe3GeTe2, and compares the structures of CrTe2, Cr5Te8, Cr2Te3, and CrTe to clarify the self-intercalation phenomenon. In addition, it summarizes the growth conditions of CrxTey using the chemical vapor deposition approach as well as commonly practiced characterization techniques for 2D ferromagnetism. This review also compares ferromagnetic properties while analyzing how Cr intercalants affect the magnetic. Finally, it suggests that more attention should be focused on this material system to unlock its full practical and academic potential, and proposes directions for future research.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)Published versionZ.L. acknowledges the support from National Research Foundation, Singapore, under its Competitive Research Program (CRP) (NRF-CRP22-2019-0007 and NRF-CRP22-2019-0004), under its NRF-ISF joint research program (NRF2020-NRF-ISF004-3520). This research is also supported by A*STAR under its AME IRG Grant (Project No. A2083c0052)

Topping-off technique prevents aggravation of degeneration of adjacent segment fusion revealed by retrospective and finite element biomechanical analysis

Aim: The aim of this study was to evaluate the effect of the Topping-off technique in preventing the aggravation of degeneration caused by adjacent segment fusion. Methods: Clinical parameters of patients who underwent L5-S1 posterior lumbar interbody fusion + interspinous process at L4-L5 (PLIF + ISP) with the Wallis system (Topping-off group) were compared retrospectively with those of patients who underwent solely PLIF. Pre- and post-operative x-ray measurements, visual analogue scale (VAS) scores, and Japanese Orthopaedic Association (JOA) scores were assessed in all subjects. Normal L1-S1 lumbosacral finite element models were established in accordance with the two types of surgery in our study, respectively. Virtual loading was added to assess the motility, disc pressure, and facet joint stress of L4-L5. Results: There were 22 and 23 valid cases included in the Topping-off and PLIF groups. No degeneration was observed in either group. Both VAS and JOA scores improved significantly post-operatively (P < 0.01). The intervertebral angle and lumbar lordosis of L4-L5 were both significantly increased (t = -2.89 and -2.68, P < 0.05 in the Topping-off group and t = -2.25 and -2.15, P < 0.05 in the PLIF group). In the Topping-off group, x-ray in dynamic position showed no significant difference in the angulation or distance of the anterior movement of the L4-L5 segment. The angle of hyper-extension and distance of the posterior movement of L4 were significantly decreased. In the PLIF group, both hyper-flexion and hyper-extension and posterior movement were increased significantly. In finite element analysis, displacement of the L4 vertebral body, pressure of the annulus fibrosus and nucleus pulposus, and stress of the bilateral facet joint were less in the Topping-off group under loads of anterior flexion and posterior extension. Facet joint stress on the left side of the L4-L5 segment was also less in the Topping-off group under left flexion loads. Conclusion: Short-term efficacy and safety between Topping-off and PLIF were similar, whilst the Topping-off technique could restrict the hyper-extension movement of adjacent segments, prevent back and forth movement of proximal vertebrae, and decrease loads of intervertebral disc and facet joints.OrthopedicsSCI(E)[email protected]

Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney diseaseResearch in context

Background: Acute kidney injury (AKI) may lead to the development of chronic kidney disease (CKD), i.e. AKI-CKD transition, but the underlying mechanism remains largely unclear. Endoplasmic reticulum (ER) stress is characterized by the accumulation of unfolded or misfolded proteins in ER resulting in a cellular stress response. The role of ER stress in AKI-CKD transition remains unknown. Methods: In this study, we examined ER stress in the mouse model of AKI-CKD transition after unilateral renal ischemia-reperfusion injury (uIR). To determine the role of ER stress in AKI-CKD transition, we tested the effects of two chemical chaperones: Tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA). Findings: uIR led to the induction of ER stress in kidneys, as indicated by increased expression of UPR molecules CHOP (C/EBP homologous protein) and BiP(binding immunoglobulin protein; also called GRP78–78 kDa glucose­regulated protein). Given at 3 days after uIR, both TUDCA and 4-PBA blocked ER stress in post-ischemic kidneys. Notably, both chemicals promoted renal recovery and suppressed tubulointerstitial injury as manifested by the reduction of tubular atrophy, renal fibrosis and myofibroblast activation. Inhibition of ER stress further attenuated renal tubular epithelial cell apoptosis, inflammation and autophagy in post-ischemic kidneys. Interpretation: These findings suggest that ER stress contributes critically to the development of chronic kidney pathologies and CKD following AKI, and inhibition of ER stress may represent a potential therapeutic strategy to impede AKI-CKD transition. Keywords: ER stress, AKI-CKD transition, Renal ischemia-reperfusion, Fibrosis, Apoptosis, Autophag

HDAC6 Inhibition Alleviates Ischemia- and Cisplatin-Induced Acute Kidney Injury by Promoting Autophagy

Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin. HDAC6 dysfunction is associated with several pathological conditions in renal disorders, including UUO-induced fibrotic kidneys and rhabdomyolysis-induced nephropathy. However, the role of HDAC6 in ischemic acute kidney injury (AKI) and the mechanism by which HDAC6 inhibition protects tubular cells after AKI remain unclear. In the present study, we observed that HDAC6 was markedly activated in kidneys subjected to ischemia- and cisplatin (cis)-induced AKI treatment. Pharmacological inhibition of HDAC6 alleviated renal impairment and renal tubular damage after ischemia and cisplatin treatment. HDAC6 dysfunction was associated with decreased acetylation of α-tubulin at the residue of lysine 40 and autophagy. HDAC6 inhibition preserved acetyl-α-tubulin-enhanced autophagy flux in AKI and cultured tubular cells. Genetic ablation of the renal tubular (RT) Atg7 gene or pharmacological inhibition of autophagy suppressed the protective effects of HDAC6. Taken together, our study indicates that HDAC6 contributes to ischemia- and cisplatin-induced AKI by inhibiting autophagy and the acetylation of α-tubulin. These results suggest that HDAC6 could be a potential target for ischemic and nephrotoxic AKI

Combination of Bone-Modifying Agents with Immunotarget Therapy for Hepatocellular Carcinoma with Bone Metastases

Due to limited investigations about efficacy of tyrosine kinase inhibitors (TKIs) plus immune-checkpoint inhibitors (ICIs) versus TKIs alone, and effects of durations of bone modifying agents (BMAs) on the survival of patients with hepatocellular carcinoma (HCC) and bone metastases (BoM), we aim to compare the efficacy of TKIs both alone and in combination with ICIs, as well as comparing long-term and no or perioperative use of BMAs for patients with HCC and BoM. Patients with pathologically confirmed HCC and BoM were included in the study. They were stratified into the TKIs group and the TKIs + ICIs group, and the perioperative and the long-term use of BMAs group. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were calculated to assess the response to these regimes. The cumulative risk of initial skeletal-related events (SREs) was used to evaluate treatment efficacy for bone lesions. A total of 21 (33.9%) patients received TKIs (Sorafenib or Lenvatinib) alone and 41 (66.1%) received TKIs + ICIs. The combination group showed higher ORR than monotherapy group (1/21, 4.7% vs. 9/41, 22.0%; p = 0.1432); Additionally, the TKIs + ICIs group offered improved OS (18 months vs. 31 months; p = 0.015) and PFS (10 months vs. 23 months; p = 0.014), while this survival benefits were more profound in virus-infected patients than those non-infected. Prolonged OS (33 months vs. 16 months; p = 0.0048) and PFS (33 months vs. 11 months; p = 0.0027) were observed in patients with long-term use of BMAs compared with no or perioperative use of BMAs. The TKIs + ICIs combination and long-term adjuvant of BMAs may offer a survival advantage for HCC patients with BoM without severe adverse events, which requires further validations