Abstract
Tendon self-renewal is a rare occurrence because of the poor vascularization of this tissue; therefore, reconstructive surgery using autologous tendon is often performed in severe injury ...cases. However, the post-surgery re-injury rate is relatively high, and the collection of autologous tendons leads to muscle weakness, resulting in prolonged rehabilitation. Here, we introduce an induced pluripotent stem cell (iPSC)-based technology to develop a therapeutic option for tendon injury. First, we derived tenocytes from human iPSCs by recapitulating the normal progression of step-wise narrowing fate decisions in vertebrate embryos. We used single-cell RNA sequencing to analyze the developmental trajectory of iPSC-derived tenocytes. We demonstrated that iPSC-tenocyte grafting contributed to motor function recovery after Achilles tendon injury in rats via engraftment and paracrine effects. The biomechanical strength of regenerated tendons was comparable to that of healthy tendons. We suggest that iPSC-tenocytes will provide a therapeutic option for tendon injury.
In this issue of Journal of Hepatology, Aji T and Dong JH et al describe the largest reported case series of 69 patients with end-stage hepatic AE who underwent ex vivo liver resection and ...autotransplantation. The patients' clinical characteristics and clinical outcomes reported in this paper provide further support for the use of ex vivo surgery in this unique population. In this series, an unresectable lesion was defined as having extensive involvement with hepatic veins or retrohepatic vena cava.
The paraventricular thalamic nucleus (PVT) is a part of epithalamus and sends outputs to emotion-related brain areas such as the medial prefrontal cortex, nucleus accumbens, and amygdala. Various ...functional roles of the PVT in emotion-related behaviors are drawing attention. Here, we investigated the effect of manipulation of PVT neurons on the firing patterns of medial prefrontal cortical (mPFC) neurons and depression-like behavior. Extracellular single-unit recordings revealed that acute activation of PVT neurons by hM3Dq, an activation type of designer receptors exclusively activated by designer drugs (DREADDs), and administration of clozapine N-oxide (CNO) caused firing rate changes in mPFC neurons. Moreover, chronic presynaptic inhibition in PVT neurons by tetanus toxin (TeTX) increased the proportion of interneurons among firing neurons in mPFC and shortened the immobility time in the forced swimming test, whereas long-term activation of PVT neurons by hM3Dq caused recurrent hypoactivity episodes. These findings suggest that PVT neurons regulate the excitation/inhibition balance in the mPFC and mood stability.
Although mitochondrial and serotonergic dysfunctions have been implicated in the etiology of bipolar disorder (BD), the relationship between these unrelated pathways has not been elucidated. A family ...of BD and chronic progressive external ophthalmoplegia (CPEO) caused by a mutation of the mitochondrial adenine nucleotide translocator 1 (ANT1, SLC25A4) implicated that ANT1 mutations confer a risk of BD. Here, we sequenced ANT1 in 324 probands of NIMH bipolar disorder pedigrees and identified two BD patients carrying heterozygous loss-of-function mutations. Behavioral analysis of brain specific Ant1 heterozygous conditional knockout (cKO) mice using lntelliCage showed a selective diminution in delay discounting. Delay discounting is the choice of smaller but immediate reward than larger but delayed reward and an index of impulsivity. Diminution of delay discounting suggests an increase in serotonergic activity. This finding was replicated by a 5-choice serial reaction time test. An anatomical screen showed accumulation of COX (cytochrome c oxidase) negative cells in dorsal raphe. Dorsal raphe neurons in the heterozygous cKO showed hyperexcitability, along with enhanced serotonin turnover in the nucleus accumbens and upregulation of Maob in dorsal raphe. These findings altogether suggest that mitochondrial dysfunction as the genetic risk of BD may cause vulnerability to BD by altering serotonergic neurotransmission.
IMPORTANCE: Long-term oncologic outcomes of robotic surgery remain a hotly debated topic in surgical oncology, but sparse data have been published thus far. OBJECTIVE: To analyze short- and long-term ...outcomes of robotic liver resection (RLR) for hepatocellular carcinoma (HCC) from Western high-volume centers to assess the safety, reproducibility, and oncologic efficacy of this technique. DESIGN, SETTING, AND PARTICIPANTS: This cohort study evaluated the outcomes of patients receiving RLR vs open liver resection (OLR) for HCC between 2010 and 2020 in 5 high-volume centers. After 1:1 propensity score matching, a group of patients who underwent RLR was compared with a validation cohort of OLR patients from a high-volume center that did not perform RLR. MAIN OUTCOMES AND MEASURES: A retrospective analysis was performed of prospectively maintained databases at 2 European and 2 US institutions of patients who underwent RLR for HCC between January 1, 2010, and September 30, 2020. The main outcomes were safety and feasibility of RLR for HCC and its oncologic outcomes compared with a European OLR validation cohort. A 2-sided P < .05 was considered significant. RESULTS: The study included 398 patients (RLR group: 125 men, 33 women, median IQR age, 66 58-71 years; OLR group: 315 men, 83 women; median IQR age, 70 64-74 years), and 106 RLR patients were compared with 106 OLR patients after propensity score matching. The RLR patients had a significantly longer operative time (median IQR, 295 190-370 minutes vs 200 165-255 minutes, including docking; P < .001) but a significantly shorter hospital length of stay (median IQR, 4 3-6 days vs 10 7-13 days; P < .001) and a lower number of admissions to the intensive care unit (7 6.6% vs 21 19.8%; P = .002). Incidence of posthepatectomy liver failure was significantly lower in the RLR group (8 7.5% vs 30 28.3%; P = .001), with no cases of grade C failure. The 90-day overall survival rate was comparable between the 2 groups (RLR, 99.1% 95% CI, 93.5%-99.9%; OLR, 97.1% 95% CI, 91.3%-99.1%), as was the cumulative incidence of death related to tumor recurrence (RLR, 8.8% 95% CI, 3.1%-18.3%; OLR, 10.2% 95% CI, 4.9%-17.7%). CONCLUSIONS AND RELEVANCE: This study represents the largest Western experience to date of full RLR for HCC. Compared with OLR, RLR performed in tertiary centers represents a safe treatment strategy for patients with HCC and those with compromised liver function while achieving oncologic efficacy.
Background Local hemostatic agents are important for the control of bleeding during liver resection when standard surgical techniques are insufficient. Study Design This was a multicenter, ...randomized, open-label study to compare fibrin sealant patch (FSP; TachoSil; Takeda Pharma A/S) with oxidized regenerated cellulose gauze (ORCG; Surgicel Original; Ethicon) for the secondary treatment of local bleeding after hepatic resection in adult and pediatric patients. Primary end point was the proportion of adult patients with intraoperative hemostasis at the target bleeding site within 3 minutes of application of treatment. Results Of 321 adult patients screened, 224 patients had minor to moderate bleeding from the hepatic resection area after primary hemostatic treatment and were intraoperatively randomized to FSP (n = 114) or ORCG (n = 110). Hemostasis within 3 minutes was achieved in 92 patients in the FSP group (80.7%) and 55 patients in the ORCG group (50.0%) (odds ratio = 4.87; 95% CI, 2.55–9.29; p < 0.001). The proportion of patients with hemostasis at 5 minutes was also higher in the FSP group (94.7% vs 76.4%; odds ratio = 6.24; 95% CI, 2.39–16.30; p < 0.001), and time to hemostasis was shorter (p < 0.001). At 10 minutes, hemostasis was achieved in all patients in the FSP group and 12 patients in the ORCG group (10.9%) had visible bleeding and required hemostatic rescue therapy. In pediatric patients, hemostasis at 3 minutes was achieved in 17 of 20 (85.0%) patients with FSP and 4 of 9 (44.4%) patients with ORCG. Both treatments were well tolerated in adults and children. Conclusions The FSP (TachoSil) was safe and superior to ORCG (Surgicel Original) for achieving hemostasis in patients undergoing hepatic resection. ClinicalTrials.gov ID NCT01192022.
Human induced pluripotent stem cells (iPSCs) are expected to be useful for regenerative medicine for many diseases. Many researchers have focused on and enabled the generation of differentiated cells ...or tissue-like structures, including organoids, which help to ameliorate target diseases. To promote such cell therapies, we established a clinically applicable iPSC haplobank matching as many people as possible in Japan.
Through cooperation with several organizations, we recruited donors whose human leukocyte antigens (HLAs) involved in immunorejection were homozygous. The peripheral or umbilical cord blood collected from the donors was used for iPSC production by electroporation of episomal vectors. These iPSC lines were then subjected to testing, including genome analyses and sterility, to maximize safety.
We constructed a clinical-grade haplobank of 27 iPSC lines from 7 donors according to good manufacturing practice regulations. However, reasons to avoid using iPSC lines include the presence of residual episomal vectors or genetic mutations in cancer-related genes.
This haplobank provides HLA-matched iPSC lines for approximately 40% of the Japanese population. Since the haplobank’s release in 2015, these iPSC lines have been used in more than 10 clinical trials. The establishment of this haplobank is an important step toward the clinical application of iPSCs in cell therapies.
This study was supported by a research center network for the realization of regenerative medicine of the Japan Agency for Medical Research and Development (AMED) under grant number JP20bm0104001h0108.
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•A clinical-grade iPSC haplobank was established from seven HLA-homozygous donors•After screening and release tests, 27 iPSC lines were selected for clinical usage•Pluripotency of iPSC lines was confirmed in vitro•The established iPSC haplobank has been used in more than 10 clinical trials
Human induced pluripotent stem cells (iPSCs), which can differentiate into many kinds of cells, have the potential to bring regenerative medicine to the treatment of many diseases. Here, scientists from the Center for iPS Cell Research and Application (CiRA) at Kyoto University and CiRA Foundation in Japan report the establishment of a clinical-grade iPSC “haplobank” that could be used in 40% of the Japanese population with little risk of rejection. These iPSC lines have already been used in more than 10 clinical trials.
Producing haplobanks of human iPSC lines from HLA-homozygous donors is a potentially cost- and time-effective strategy to match large populations. Here, Yoshida et al. construct a clinical-grade haplobank of 27 iPSC lines matching 40% of the Japanese population, which have already been used in more than 10 clinical trials.
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