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Salivary gland hypofunction, also known as xerostomia, occurs as a result of radiation therapy for head cancer, Sjögren’s syndrome or aging, and can cause a variety of critical oral health issues, including dental decay, bacterial infection, mastication dysfunction, swallowing dysfunction and reduced quality of life. Here we demonstrate the full functional regeneration of a salivary gland that reproduces the morphogenesis induced by reciprocal epithelial and mesenchymal interactions through the orthotopic transplantation of a bioengineered salivary gland germ as a regenerative organ replacement therapy. The bioengineered germ develops into a mature gland through acinar formations with a myoepithelium and innervation. The bioengineered submandibular gland produces saliva in response to the administration of pilocarpine and gustatory stimulation by citrate, protects against oral bacterial infection and restores normal swallowing in a salivary gland-defective mouse model. This study thus provides a proof-of-concept for bioengineered salivary gland regeneration as a potential treatment of xerostomia. Salivary gland dysfunction as a result of diseases or ageing reduces the quality of life and causes various oral health problems. Here the authors show that the salivary gland function of mice can be recovered by orthotopic transplantation of a bioengineered salivary gland germ.

Glycolysis is the metabolic pathway that converts glucose into pyruvate, whereas fermentation can then produce lactate from pyruvate. Here, we developed single fluorescent protein (FP)-based lactate and pyruvate indicators with low EC 50 for trace detection of metabolic molecules and live cell imaging and named them “Green Lindoblum” and “Green Pegassos,” respectively. Green Lindoblum (EC 50 of 30 µM for lactate) and Green Pegassos (EC 50 of 70 µM for pyruvate) produced a 5.2- and 3.3-fold change in fluorescence intensity in response to lactate and pyruvate, respectively. Green Lindoblum measured lactate levels in mouse plasma, and Green Pegassos in combination with D-serine dehydratase successfully estimated D-serine levels released from mouse primary cultured neurons and astrocytes by measuring pyruvate level. Furthermore, live cell imaging analysis revealed their utility for dual-colour imaging, and the interplay between lactate, pyruvate, and Ca 2+ in human induced pluripotent stem cell-derived cardiomyocytes. Therefore, Green Lindoblum and Green Pegassos will be useful tools that detect specific molecules in clinical use and monitor the interplay of metabolites and other related molecules in diverse cell types.

The lacrimal gland has a multifaceted role in maintaining a homeostatic microenvironment for a healthy ocular surface via tear secretion. Dry-eye disease, which is caused by lacrimal gland dysfunction, is one of the most prevalent eye diseases that cause corneal epithelial damage and results in significant loss of vision and a reduction in the quality of life. Here we demonstrate orthotopic transplantation of bioengineered lacrimal gland germs into adult mice with an extra-orbital lacrimal gland defect, a mouse model that mimics the corneal epithelial damage caused by lacrimal gland dysfunction. The bioengineered lacrimal gland germs and harderian gland germs both develop in vivo and achieve sufficient physiological functionality, including tear production in response to nervous stimulation and ocular surface protection. This study demonstrates the potential for bioengineered organ replacement to functionally restore the lacrimal gland. Lacrimal glands maintain a healthy corneal epithelium but are dysfunctional for example in dry-eye disease. Here, the authors transplant bioengineered lacrimal and harderian gland germs into mice, where they connect to the host duct and nervous system and restore lacrimal gland function.

Fatty acids are known to have significant effects on the properties of cancer cells. Therefore, these compounds have been incorporated into therapeutic strategies. However, few studies have examined the effects of individual fatty acids and their interactions in depth. This study analyzed the effects of various fatty acids on cancer cells and revealed that stearic acid, an abundant saturated fatty acid, had a stronger inhibitory effect on cell growth than did palmitic acid, which is also an abundant saturated fatty acid, by inducing DNA damage and apoptosis through the unfolded protein response (UPR) pathway. Intriguingly, the negative effects of stearate were reduced by the presence of oleate, a different type of abundant fatty acid. We combined a stearate-rich diet with the inhibition of stearoyl-CoA desaturase-1 to explore the impact of diet on tumor growth. This intervention significantly reduced tumor growth in both ovarian cancer models and patient-derived xenografts (PDXs), including those with chemotherapy resistance, notably by increasing stearate levels while reducing oleate levels within the tumors. Conversely, the negative effects of a stearate-rich diet were mitigated by an oleate-rich diet. This study revealed that dietary stearate can directly inhibit tumor growth through mechanisms involving DNA damage and apoptosis mediated by the UPR pathway. These results suggest that dietary interventions, which increase stearic acid levels while decreasing oleic acid levels, may be promising therapeutic strategies for cancer treatment. These results could lead to the development of new cancer treatment strategies. Stearic Acid Inhibits Cancer Growth Through DNA Damage Obesity, characterized by excessive body fat, is linked to higher cancer risks. Researchers explored how specific fatty acids impact cancer growth. The study focused on palmitate, stearate, and oleate, using various cancer cell lines and patient derived xenograft. They found that stearate significantly inhibited cancer cell growth more than palmitate. This was a controlled experiment involving human cancer cell lines and mice fed specialized diets. Results showed that stearate induced DNA damage and cancer cell death, while oleate reduced these effects. The researchers concluded that dietary stearate could suppress tumor growth, especially when combined with inhibitors of fatty acid conversion. Future research could explore dietary interventions as potential cancer treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Current approaches to the development of regenerative therapies have been influenced by our understanding of embryonic development, stem cell biology, and tissue engineering technology. The ultimate goal of regenerative therapy is to develop fully functioning bioengineered organs which work in cooperation with surrounding tissues to replace organs that were lost or damaged as a result of disease, injury, or aging. Here, we report a successful fully functioning tooth replacement in an adult mouse achieved through the transplantation of bioengineered tooth germ into the alveolar bone in the lost tooth region. We propose this technology as a model for future organ replacement therapies. The bioengineered tooth, which was erupted and occluded, had the correct tooth structure, hardness of mineralized tissues for mastication, and response to noxious stimulations such as mechanical stress and pain in cooperation with other oral and maxillofacial tissues. This study represents a substantial advance and emphasizes the potential for bioengineered organ replacement in future regenerative therapies.

To bioengineer ectodermal organs such as teeth and whisker follicles, we developed a three-dimensional organ-germ culture method. The bioengineered tooth germ generated a structurally correct tooth, after both in vitro organ culture as well as transplantation under a tooth cavity in vivo , showing penetration of blood vessels and nerve fibers. Our method provides a substantial advance in the development of bioengineered organ replacement strategies and regenerative therapies. Please visit methagora to view and post comments on this article

BackgroundThe novel fourth-generation cryoballoon (4th-CB) is characterized by a shorter-tip that potentially facilitates better time-to-isolation (TTI) monitoring. We sought to clarify the advantages and disadvantages of the 4th-CB compared to the second-generation cryoballoon (2nd-CB) in pulmonary vein isolation (PVI).MethodsForty-one and 49 consecutive atrial fibrillation patients underwent 2nd-CB and 4th-CB PVIs using 28-mm balloons and short freeze strategies. When effective freezing was not obtained, the CB was switched to the other CB.ResultsThe rate of successful PVIs was significantly higher for 2nd-CBs than 4th-CBs (162/162[100%] vs. 178/193[92.2%] PVs, p < 0.0001). The difference was significant for lower PVs, especially right inferior PVs (RIPVs)(p = 0.005). In a total of 15 PVs in 11 patients, 4th-CBs were switched to 2nd-CBs, and 14/15(93.3%) PVs were successfully isolated. The balloon temperature tended to reach -55℃ more frequently with 2nd-CBs than 4th-CBs during RIPV ablations (15/41[36.6%] vs. 12/49[24.5%], p = 0.21). The TTI monitoring capability was significantly higher with 4th-CBs than 2nd-CBs (131/188[69.7%] vs. 83/160[51.9%] PVs, p = 0.0007). The difference was significant for right superior and left inferior PVs, but not for left superior PVs. Even if PVs requiring crossover were excluded, the total freeze duration (715±152 vs. 755±215 seconds, p = 0.31) tended to be shorter for 2nd-CBs than 4th-CBs. The incidence of phrenic nerve injury was similar for 2nd-CB and 4th-CB ablation (0/41 vs. 2/49, p = 0.12)ConclusionsThe 4th-CB’s shorter balloon tip enabled a significantly higher capability of TTI monitoring; however, it resulted in significantly lower rates of successful PVIs than the 2nd-CB, especially for the RIPVs.

BackgroundDetailed mapping studies of accessory pathway (AP) conduction have not been previously performed using ultra-high resolution mapping systems. We sought to evaluate the clinical utility of ultra-high resolution mapping systems and the novel “Lumipoint” algorithm in AP ablation.MethodsThis study included 17 patients who underwent AP mapping using minielectrode basket catheters and Rhythmia systems. Ablation was performed with 4-mm irrigated-tip catheters. ResultsAntegrade and retrograde AP conduction was observed in 6 and 16 patients. Atrial activation map was obtained during orthodromic tachycardia and ventricular pacing in 13 (76.5%) and 14 (82.3%) patients, and the earliest activation area was identical. Ventricular activation maps were created during atrial pacing in 3 patients. All maps showed focal activation patterns on global activation histograms, and the valley on the histogram highlighted the earliest activation area. “Complex activation” features further highlighted limited areas with continuous electrical activity during the time period in the majority. APs were located at the mitral and tricuspid annuli in 15 and 2 patients, and all were successfully eliminated with 3.4 ± 0.6 s applications. No patients had recurrences during a median follow-up of 15 [10.5–22.5] months. At successful ablation sites, the local atrial and ventricular electrogram amplitudes and ratio tended to be greater, and fusion or continuous electrical activity between the atrial and ventricular components was more frequently observed on the minielectrode than ablation catheter (17/17 vs. 12/17, p = 0.005).ConclusionsUltra-high resolution activation mapping and a novel algorithm facilitated the AP localization. The local electrogram characteristics differed between the minielectrode and ablation catheters.

Motions of circular and linear DNA molecules of various lengths near a nanopore of 100 or 200 nm diameter were experimentally observed and investigated by fluorescence microscopy. The movement of DNA molecules through nanopores, known as translocation, is mainly driven by electric fields near and inside the pores. We found significant clogging of nanopores by DNA molecules, particularly by circular DNA and linear T4 DNA (165.65 kbp). Here, the probabilities of DNA clogging events, depending on the DNA length and shape—linear or circular—were determined. Furthermore, two distinct DNA motions were observed: clog and release by linear T4 DNA, and a reverse direction motion at the pore entrance by circular DNA, after which both molecules moved away from the pore. Finite element method-based numerical simulations were performed. The results indicated that DNA molecules with pores 100–200 nm in diameter were strongly influenced by opposing hydrodynamic streaming flow, which was further enhanced by bulky DNA configurations.

For gestational trophoblastic neoplasia (GTN) affecting women of reproductive age, the chemotherapy-first approach is often preferred over the surgery-first approach. Low-risk GTN is treated with a chemotherapy-first approach, but the number of courses required can affect fertility. A surgery-first approach may decrease the number of chemotherapy courses, but its efficacy and safety compared to a chemotherapy-first approach are unclear. Thus, we investigated the efficacy and safety of the surgery-first approach compared to the chemotherapy-first approach in treating low-risk GTN. We searched the MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform databases for relevant articles in July 2023. A systematic review and meta-analysis of outcome measures were conducted using a random-effects model. The primary outcomes were remission, the mean number of chemotherapy courses required to cure, and adverse events. The certainty of the evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation approach. This study protocol was registered in the Open Science Framework (https://osf.io/kysvn/). Studies for low-risk GTN included a qualitative synthesis (with 2,192 participants and ten studies, eight of which were about second uterine curettage and two about hysterectomy) and a meta-analysis (with 138 participants and two randomized controlled trials (RCTs) that compared first-line treatments of second uterine curettage and chemotherapy). Second uterine curettage may result in little to no difference in remission (risk ratio: 1.00, 95% confidence interval: 0.96-1.05; low certainty) and a slight reduction in adverse events (risk ratio: 0.87, 95% confidence interval: 0.47-1.60; low certainty). The evidence is very uncertain on the mean number of chemotherapy courses (mean difference: 2.84 lower, 95% confidence interval: 7.31 lower to 1.63 higher; very low certainty). Based on clinical outcomes, second uterine curettage can be comparable to the chemotherapy-first approach as a first-line treatment option for low-risk GTN; however, the overall certainty of the evidence was low or very low.