Real-time lung weight measurement during clinical ex vivo lung perfusion.

BACKGROUND: Real-time lung weight (LW) measurement is a simple and non-invasive technique for detecting extravascular lung water during ex vivo lung perfusion (EVLP). We investigated the feasibility of real-time LW measurement in clinical EVLP as a predictor of transplant suitability and post-transplant outcomes. METHODS: In our clinical acellular EVLP protocol, real-time LW was measured in 117 EVLP cases from June 2019 to June 2022. The estimated LW gain at each timepoint was calculated using a scale placed under the organ chamber. The lungs were classified into four categories based on LW adjusted for height and compared between suitable and unsuitable cases. The relationship between estimated LW gain and primary graft dysfunction was also investigated. RESULTS: The estimated LW gain during the EVLP significantly correlated with the LW gain (post EVLP LW - pre EVLP LW) measured on the back table (R2=0.61, P<0.01). In the adjusted LW categories 2-4, the estimated LW gain at 0-1 h after EVLP was significantly higher in unsuitable cases than in suitable cases. The area under the curve for the estimated LW gain was ≥0.80. Primary graft dysfunction grade 0-1 had a significantly lower estimated LW gain at 60 min than grades 2-3 (-43 vs. 1 g, P<0.01). CONCLUSIONS: Real-time lung measurements can predict transplant suitability and post-transplant outcomes by the early detection of extravascular lung water during the initial 1 h of EVLP.

Exploring the Potential Use of Natural Products Together with Alkalization in Cancer Therapy.

Cancer treatment is a significant focus in medicine, owing to the increasing global incidence of cancers. Patients with advanced cancers that do not respond to conventional therapies have limited options and an unfavorable prognosis. Consequently, researchers are investigating complementary approaches to conventional treatments. One such approach is alkalization therapy, which aims to neutralize the acidic tumor microenvironment (TME) by increasing its pH level. The acidic TME promotes inflammation, tumor progression, and drug resistance. Alkalization therapy has been demonstrated to be effective for various cancers. In addition, natural products, such as triterpenoids, parthenolides, fulvic acid, Taxus yunnanensis, and apple pectin have the potential to alleviate symptoms, maintain physical fitness, and improve treatment outcomes of cancer patients through their anti-inflammatory, antioxidant, and anticancer properties. In this review, we focus on the effects of alkalization therapy and natural products on cancer. Furthermore, we present a case series of advanced cancer patients who received alkalization therapy and natural products alongside standard treatments, resulting in long-term survival. We posit that alkalization therapy together with supplementation with natural products may confer benefits to cancer patients, by mitigating the side effects of chemotherapy and complementing standard treatments. However, further research is warranted to validate these clinical findings.

Squamous cell carcinoma of mandibular gingiva producing both parathyroid hormone-related protein and granulocyte colony-stimulating factor: a case report.

We describe a case of mandibular gingival carcinoma with hypercalcaemia and leukocytosis caused by tumour-derived parathyroid hormone-related protein (PTHrP) and granulocyte colony-stimulating factor (G-CSF). A 54-year-old man presented to our Department of Oral and Maxillofacial Surgery with a chief complaint of a left-sided mandibular gingival ulcer. A 42 mm × 20 mm sized ulcer was found on the left lower molar gingiva. Squamous cell carcinoma was pathologically diagnosed. The patient underwent a hemimandibulectomy, left-sided radical neck dissection, plate reconstruction, pectoralis major musculocutaneous flap reconstruction, and tracheostomy under general anaesthesia. Pathologically, two metastatic lymph nodes were identified. Residual tumour was suspected at the resection margins. Eight weeks after surgery, the patient started postoperative concurrent chemoradiotherapy (CCRT). Two weeks after CCRT, the patient developed hypercalcaemia. Serum levels of PTHrP and G-CSF increased in parallel with the progression of hypercalcaemia and leukocytosis. Immunohistochemical analysis of the surgical specimen showed positivity for G-CSF. Based on these clinical and pathological findings, the patient was diagnosed with hypercalcaemia and leukocytosis associated with malignancy and was treated with denosumab. Irradiation was terminated at 50 Gy because CT showed rapid disease progression. Chemotherapy was initiated, however, four weeks after the start of chemotherapy, a CT scan showed increased metastases and pleural dissemination. Therefore, chemotherapy was discontinued. One week after the chemotherapy was discontinued, the patient died of respiratory failure.

Intermittent Ex Vivo Lung Perfusion in a Porcine Model for Prolonged Lung Preservation.

BACKGROUND: Ex vivo lung perfusion expands the lung transplant donor pool and extends preservation time beyond cold static preservation. We hypothesized that repeated regular ex vivo lung perfusion would better maintain lung grafts. METHODS: Ten pig lungs were randomized into 2 groups. The control underwent 16 h of cold ischemic time and 2 h of cellular ex vivo lung perfusion. The intermittent ex vivo lung perfusion group underwent cold ischemic time for 4 h, ex vivo lung perfusion (first) for 2 h, cold ischemic time for 10 h, and 2 h of ex vivo lung perfusion (second). Lungs were assessed, and transplant suitability was determined after 2 h of ex vivo lung perfusion. RESULTS: The second ex vivo lung perfusion was significantly associated with better oxygenation, limited extravascular water, higher adenosine triphosphate, reduced intraalveolar edema, and well-preserved mitochondria compared with the control, despite proinflammatory cytokine elevation. No significant difference was observed in the first and second perfusion regarding oxygenation and adenosine triphosphate, whereas the second was associated with lower dynamic compliance and higher extravascular lung water than the first. Transplant suitability was 100% for the first and 60% for the second ex vivo lung perfusion, and 0% for the control. CONCLUSIONS: The second ex vivo lung perfusion had a slight deterioration in graft function compared to the first. Intermittent ex vivo lung perfusion created a better condition for lung grafts than cold static preservation, despite cytokine elevation. These results suggested that intermittent ex vivo lung perfusion may help prolong lung preservation.

Asymmetrically Functionalized Electron-Deficient π-Conjugated System for Printed Single-Crystalline Organic Electronics.

Large-area single-crystalline thin films of n-type organic semiconductors (OSCs) fabricated via solution-processed techniques are urgently demanded for high-end electronics. However, the lack of molecular designs that concomitantly offer excellent charge-carrier transport, solution-processability, and chemical/thermal robustness for n-type OSCs limits the understanding of fundamental charge-transport properties and impedes the realization of large-area electronics. The benzo[de]isoquinolino[1,8-gh]quinolinetetracarboxylic diimide (BQQDI) π-electron system with phenethyl substituents (PhC2 -BQQDI) demonstrates high electron mobility and robustness but its strong aggregation results in unsatisfactory solubility and solution-processability. In this work, an asymmetric molecular design approach is reported that harnesses the favorable charge transport of PhC2 -BQQDI, while introducing alkyl chains to improve the solubility and solution-processability. An effective synthetic strategy is developed to obtain the target asymmetric BQQDI (PhC2 -BQQDI-Cn ). Interestingly, linear alkyl chains of PhC2 -BQQDI-Cn (n = 5-7) exhibit an unusual molecular mimicry geometry with a gauche conformation and resilience to dynamic disorders. Asymmetric PhC2 -BQQDI-C5 demonstrates excellent electron mobility and centimeter-scale continuous single-crystalline thin films, which are two orders of magnitude larger than that of PhC2 -BQQDI, allowing for the investigation of electron transport anisotropy and applicable electronics.

Innsbruck-style Retromandibular Anterior Trans-parotid Approach for Condylar Fractures: A Retrospective Review of 39 Fractures.

The retromandibular anterior trans-parotid (RAT) approach and a triangular-positioned double mini-plate osteosynthesis (TDO) technique have been reported from Innsbruck Medical University. This minimally invasive technique involves direct visualization of the condyle and is associated with lower incidence of facial palsy. Methods: A retrospective review was performed on the RAT approach and TDO technique conducted by a surgeon and team at two hospitals in Tokyo during a period of 3 years and 10 months. Results: This technique was performed on 35 patients with 39 condylar fractures. Sixty-nine percent of cases were due to accidental fall, 17% to traffic accidents, and 9% to sports. Furthermore, 92% cases were condylar base fractures. Nighty-seven percent of cases achieved good occlusion. The mean maximum mouth opening was 49 ± 1.3 mm. Postoperatively, facial palsy developed in three patients (7.7%), and two of them developed Frey syndrome at approximately 2.5 years postoperatively (5.1%). All patients completely recovered within 3 months postoperatively. One case each of salivary fistula, visible scar, and condylar resorption was found (2.6%). No case of massive bleeding during surgery, hematoma, or TMJ pain after surgery was found. Conclusion: This technique could achieve good occlusion with low incidence of complications and could contribute to early social reintegration among patients.

Individual and synergetic charge transport properties at the solid and electrolyte interfaces of a single ultrathin single crystal of organic semiconductors.

The chemical structures and morphologies of organic semiconductors (OSCs) and gate dielectrics have been widely investigated to improve the electrical performances of organic thin-film transistors (OTFTs) because the charge transport therein is a phenomenon at the semiconductor-dielectric interfaces. Here, solid and ionic gel gate dielectrics were adopted on the lower and upper surfaces, respectively, of a single, two molecule-thick single crystals of p-type OSCs to study the charge transport properties at individual interfaces between the morphologically compatible OSC surface and different gate dielectrics. Using the four-probe method, the solid and ionic gel interfaces were found to exhibit hole mobilities of 9.3 and 2.2 cm2 V-1 s-1, respectively, which revealed the crucial impact of the gate dielectric materials on the interfacial charge transport. Interestingly, when gate biases are applied through both dielectrics, i.e., under the solid/ionic gel dual-gate transistor operation, the hole mobility at the solid gate interface is improved up to 14.7 cm2 V-1 s-1, which is 1.5 times greater than that assessed without the ionic gel gate. This improvement can be attributed to the electric double layer formed at the ionic gel/uniform crystal surface, which provides a close-to-ideal charge transport interface through dramatic trap-filling. Therefore, the present dual-gate transistor technique will be promising for investigating the intrinsic charge-transport capabilities of OSCs.

Crown ether salt-doped ladder-type conducting polymers for air-stable n-type thermoelectric materials.

Thermoelectric energy harvesters based on p- and n-type organic semiconductors are in high demand, while the air stability of n-type devices has long been a challenge. Here, we demonstrate that supramolecular salt-functionalized n-doped ladder-type conducting polymers exhibit excellent stability in the presence of dry air.

Left ventricular assist device mode: Co-pulse left ventricular unloading in a working mode of ex vivo heart perfusion.

BACKGROUND: For normothermic ex vivo heart perfusion (EVHP), a resting mode and working mode have been proposed. We newly developed a left ventricular assist device (LVAD) mode that supports heart contraction by co-pulse synchronized LVAD. METHODS: Following resting mode during time 0 to 1 hour, pig hearts (n = 18) were perfused in either resting, working, or LVAD mode during time 1 to 5 hour, and then myocardial function was evaluated in working mode at 6 hour. The preservation ratio was defined as the myocardial mechanical function at 330 minute divided by the function at 75 minute. In LVAD mode, LVAD unloaded the pressure and the volume in the left ventricle in the systolic phase. RESULTS: The LVAD group was significantly associated with higher preservation ratios in cardiac output (resting, 33 ± 3; working, 35 ± 5; LVAD, 76% ± 5%; p < 0.001), stroke work, dP/dt maximum, and dP/dt minimum compared with the other groups. Glucose consumption was significantly reduced in the resting group. The LVAD group was significantly associated with higher myocardial oxygen consumption (resting, 2.2 ± 0.3; working; 4.6 ± 0.5; LVAD, 6.1 ± 0.5 mL O2/min/100 g, p < 0.001) and higher adenosine triphosphate (ATP) levels (resting, 1.1 ± 0.1; working, 0.7 ± 0.1; LVAD, 1.6 ± 0.2 µmol/g, p = 0.001) compared with the others. CONCLUSION: These data suggest that myocardial mechanical function was better preserved in LVAD mode than in resting and working modes. Although our data suggested similar glycolysis activity in the LVAD and working groups, the higher final ATP in the LVAD group might be explained by reduced external work in LVAD.

Real-time Lung Weight Measurement During Cellular Ex Vivo Lung Perfusion: An Early Predictor of Transplant Suitability.

BACKGROUND: Increased extravascular lung water during ex vivo lung perfusion (EVLP) is associated with ischemia reperfusion injury and poor pulmonary function. A non-invasive technique for evaluating extravascular lung water during EVLP is desired to assess the transplant suitability of lungs. We investigated real-time lung weight measurements as a reliable method for assessing pulmonary functions in cellular EVLP using a porcine lung model. METHODS: Fifteen pigs were randomly divided into 3 groups: control (no warm ischemia) or donation after circulatory death groups with 60 or 90 min of warm ischemia (n = 5, each). Real-time lung weight gain was measured by load cells positioned at the bottom of the organ chamber. RESULTS: Real-time lung weight gain at 2 h was significantly correlated with lung weight gain as measured on a back table ( R = 0.979, P < 0.01). Lung weight gain in non-suitable cases (n = 6) was significantly higher than in suitable cases (n = 9) at 40 min (51.6 ± 46.0 versus -8.8 ± 25.7 g; P < 0.01, cutoff = +12 g, area under the curve = 0.907). Lung weight gain at 40 min was significantly correlated with PaO 2 /FiO 2 , peak inspiratory pressure, shunt ratio, wet/dry ratio, and transplant suitability at 2 h ( P < 0.05, each). In non-suitable cases, lung weight gain at 66% and 100% of cardiac output was significantly higher than at 33% ( P < 0.05). CONCLUSIONS: Real-time lung weight measurement could potentially be an early predictor of pulmonary function in cellular EVLP.

Electron-Deficient Benzo[de]isoquinolino[1,8-gh]quinoline Diamide π-Electron Systems.

Synthetically versatile electron-deficient π-electron systems are urgently needed for organic electronics, yet their design and synthesis are challenging due to the low reactivity from large electron affinities. In this work, we report a benzo[de]isoquinolino[1,8-gh]quinoline diamide (BQQDA) π-electron system. The electron-rich condensed amide as opposed to the generally-employed imide provides a suitable electronic feature for chemical versatility to tailor the BQQDA π-electron system for various electronic applications. We demonstrate an effective synthetic method to furnish the target BQQDA parent structure, and highly selective functionalization can be performed on bay positions of the π-skeleton. In addition, thionation of BQQDA can be accomplished under mild conditions. Fine-tuning of fundamental properties and supramolecular packing motifs are achieved via chemical modifications, and the cyanated BQQDA organic semiconductor demonstrates a high air-stable electron-carrier mobility.

Potential of Alkalization Therapy for the Management of Metastatic Pancreatic Cancer: A Retrospective Study.

Current treatments for patients with pancreatic cancer offer limited benefits. In this study, we applied alkalization therapy, which was efficacious for other solid tumors at our clinic, to stage 4 pancreatic cancer patients, and investigated its effect on disease prognosis. Patients with metastatic pancreatic cancer who were treated at Karasuma Wada Clinic in Kyoto, Japan, between January 2011 and April 2022, were included in the study. All patients received alkalization therapy (a combination of an alkaline diet, bicarbonate, and citric acid administration), alongside standard chemotherapy. Urine samples were collected to assess urine pH as a marker of whole-body alkalization. In the 98 patients analyzed, the median overall survival (OS) from the time of diagnosis was 13.2 months. Patients with a mean urine pH of 7.5 or greater had a median OS of 29.9 months, compared with 15.2 months for those with a mean urine pH of 6.5 to 7.5, and 8.0 months for those with a mean urine pH of less than 6.5, which suggests a trend of a longer OS in patients with a higher urine pH (p = 0.0639). Alkalization therapy may offer a viable approach to extending the survival of stage 4 pancreatic cancer patients, who typically have an unfavorable prognosis.

Electrostatically-sprayed carbon electrodes for high performance organic complementary circuits.

Organic thin-film transistors (OTFTs) are promising building blocks of flexible printable electronic devices. Similar to inorganic FETs, OTFTs are heterostructures consisting of metals, insulators, and semiconductors, in which nanoscale interfaces between different components should be precisely engineered. However, OTFTs use noble metals, such as gold, as electrodes, which has been a bottleneck in terms of cost reduction and low environmental loading. In this study, we demonstrate that graphite-based carbon electrodes can be deposited and patterned directly onto an organic single-crystalline thin film via electrostatic spray coating. The present OTFTs exhibited reasonably high field-effect mobilities of up to 11 cm2 V-1 s-1 for p-type and 1.4 cm2 V-1 s-1 for n-type with no significant deterioration during electrostatic spray processes. We also demonstrate two significant milestones from the viewpoint of material science: a complementary circuit, an inverter consisting of p- and n-type OTFTs, and an operatable metal-free OTFT composed of fully carbon-based materials. These results constitute a key step forward in the further development of printed metal-free integrated circuits.

Experimental confirmation of self-imaging effect between guided light and surface plasmon polaritons in hybrid plasmonic waveguides.

We fabricated a hybrid plasmonic device using self-imaging effect between guided light and surface plasmon polaritons in the hybrid plasmonic waveguide. The hybrid plasmonic device was fabricated by evaporating gold on the part of the silicon waveguide. Self-imaging was generated at the gold-covered section in the waveguide. Self-imaging of guided light and surface plasmon polaritons in hybrid plasmonic waveguides affect the output intensity of the hybrid plasmonic waveguide. The length of the hybrid plasmonic waveguide changes self-imaging conditions. We confirmed that the output intensity was affected by the length of the hybrid plasmonic waveguide. These findings contribute to the development of hybrid plasmonic devices and potentially improve integration density of hybrid photonic integrated circuits.

Low levels of nitric oxide promotes heme maturation into several hemeproteins and is also therapeutic.

Nitric oxide (NO) is a signal molecule and plays a critical role in the regulation of vascular tone, displays anti-platelet and anti-inflammatory properties. While our earlier and current studies found that low NO doses trigger a rapid heme insertion into immature heme-free soluble guanylyl cyclase ß subunit (apo-sGCß), resulting in a mature sGC-αß heterodimer, more recent evidence suggests that low NO doses can also trigger heme-maturation of hemoglobin and myoglobin. This low NO phenomena was not only limited to sGC and the globins, but was also found to occur in all three nitric oxide synthases (iNOS, nNOS and eNOS) and Myeloperoxidase (MPO). Interestingly high NO doses were inhibitory to heme-insertion for these hemeproteins, suggesting that NO has a dose-dependent dual effect as it can act both ways to induce or inhibit heme-maturation of key hemeproteins. While low NO stimulated heme-insertion of globins required the presence of the NO-sGC-cGMP signal pathway, iNOS heme-maturation also required the presence of an active sGC. These effects of low NO were significantly diminished in the tissues of double (n/eNOS-/-) and triple (n/i/eNOS-/-) NOS knock out mice where lung sGC was found be heme-free and the myoglobin or hemoglobin from the heart/lungs were found be low in heme, suggesting that loss of endogenous NO globally impacts the whole animal and that this impact of low NO is both essential and physiologically relevant for hemeprotein maturation. Effects of low NO were also found to be protective against ischemia reperfusion injury on an ex vivo lung perfusion (EVLP) system prior to lung transplant, which further suggests that low NO levels are also therapeutic.

Novel Cell Therapy Using Mesenchymal Stromal Cell Sheets for Medication-Related Osteonecrosis of the Jaw.

Despite medication-related osteonecrosis of the jaw (MRONJ) being first reported in 2003, the optimal treatment and prevention modalities for MRONJ are not clear. As a result, dentistry, oral surgery, and departments involved in the treatment of cancer and bone diseases are struggling with the management of MRONJ. Several cases of MRONJ cannot be managed by conventional treatment strategies recommended in various position papers. Therefore, studies have been conducted to investigate the efficacy of novel therapies for MRONJ. However, the optimal treatment is unknown. Several cell therapies including autologous cell transplantation have been reported for MRONJ. Although the efficacy of cell therapy for MRONJ has been demonstrated, large, statistically accurate clinical trials are lacking. We have been investigating the efficacy of MRONJ treatment using mesenchymal stromal cell (MSC) sheets since 2013 and confirmed its efficacy through various experiments, wherein MSC sheets were transplanted in model rats and beagle dogs with MRONJ-like lesions. Based on these results, we are planning to conduct a clinical trial of MRONJ therapy using periodontal ligament-derived MSC sheets.

Prone ex vivo lung perfusion protects human lungs from reperfusion injury.

BACKGROUND: We previously reported beneficial effects of prone positioning during ex vivo lung perfusion (EVLP) using porcine lungs. In this study, we sought to determine if prone positioning during EVLP was beneficial in human donor lungs rejected for clinical use. METHODS: Human double lung blocs were randomized to prone EVLP (n = 5) or supine EVLP (n = 5). Following 16 h of cold storage at 4°C and 2 h of cellular EVLP in either the prone or supine position. Lung function, compliance, and weight were evaluated and transplant suitability determined after 2 h of EVLP. RESULTS: Human lungs treated with prone EVLP had significantly higher partial pressure of oxygen/fraction of inspired oxygen (P/F) ratio [348 (291-402) vs. 199 (191-257) mm Hg, p = 0.022] and significantly lower lung weight [926(864-1078) vs. 1277(1029-1483) g, p = 0.037] after EVLP. 3/5 cases in the prone group were judged suitable for transplant after EVLP, while 0/5 cases in the supine group were suitable. When function of upper vs. lower lobes was evaluated, prone EVLP lungs showed similar P/F ratios and inflammatory cytokine levels in lower vs. upper lobes. In contrast, supine EVLP lungs showed significantly lower P/F ratios [68(59-150) vs. 467(407-515) mm Hg, p = 0.012] and higher tissue tumor necrosis factor alpha levels [100.5 (46.9-108.3) vs. 39.9 (17.0-61.0) ng/ml, p = 0.036] in lower vs. upper lobes. CONCLUSIONS: Prone lung positioning during EVLP may optimize the outcome of EVLP in human donor lungs, possibly by improving lower lobe function.

Mixed-Orbital Charge Transport in N-Shaped Benzene- and Pyrazine-Fused Organic Semiconductors.

The hole-carrier transport of organic semiconductors is widely known to occur via intermolecular orbital overlaps of the highest occupied molecular orbitals (HOMO), though the effect of other occupied molecular orbitals on charge transport is rarely investigated. In this work, we first demonstrate evidence of a mixed-orbital charge transport concept in the high-performance N-shaped decyl-dinaphtho[2,3-d:2',3'-d']benzo[1,2-b:4,5-b']dithiophene (C10-DNBDT-NW), where electronic couplings of the second HOMO (SHOMO) and third HOMO (THOMO) also contribute to the charge transport. We then present the molecular design of an N-shaped bis(naphtho[2',3':4,5]thieno)[2,3-b:2',3'-e]pyrazine (BNTP) π-electron system to induce more pronounced mixed-orbital charge transport by incorporating the pyrazine moiety. An effective synthetic strategy for the pyrazine-fused extended π-electron system is developed. With substituent engineering, the favorable two-dimensional herringbone assembly can be obtained with BNTP, and the decylphenyl-substituted BNTP (C10Ph-BNTP) demonstrates large electronic couplings involving the HOMO, SHOMO, and THOMO in the herringbone assembly. C10Ph-BNTP further shows enhanced mixed-orbital charge transport when the electronic couplings of all three occupied molecular orbitals are taken into consideration, which results in a high hole mobility up to 9.6 cm2 V-1 s-1 in single-crystal thin-film organic field-effect transistors. The present study provides insights into the contribution of HOMO, SHOMO, and THOMO to the mixed-orbital charge transport of organic semiconductors.