A THERMOELECTRIC SEMICONDUCTOR DEVICE WITH A HIGH TEMPERATURE GRADIENT

In the article the thermoelectric device, which heated junctions spatially distant from the cold junctions to reduce parasitic losses between the conductive junctions

Design and synthesis of lipid-mimetic cationic iridium complexes and their liposomal formulation for in vitro and in vivo application in luminescent bioimaging

Two iridium [Ir(NC)(2)(NN)](+) complexes with the diimine NN ligand containing a long polymethylene hydrophobic chain were synthesized and characterized by using NMR and ESI mass-spectrometry: NN - 2-(1-hexadecyl-1H-imidazol-2-yl)pyridine, NC - methyl-2-phenylquinoline-4-carboxylate (Ir1) and 2-phenylquinoline-4-carboxylic acid (Ir2). These complexes were used to prepare the luminescent PEGylated DPPC liposomes (DPPC/DSPE-PEG2000/Ir-complex = 95/4.5/1 mol%) using a thin film hydration method. The narrowly dispersed liposomes had diameters of about 110 nm. The photophysics of the complexes and labeled liposomes were carefully studied. Ir1 and Ir2 give red emission (lambda(em) = 667 and 605 nm) with a lifetime in the microsecond domain and quantum yields of 4.8% and 10.0% in degassed solution. Incorporation of the complexes into the liposome lipid bilayer results in shielding of the emitters from interaction with molecular oxygen and partial suppression of excited state nonradiative relaxation due to the effect of the relatively rigid bilayer matrix. Delivery of labeled liposomes to the cultured ARPE-19 cells demonstrated the usefulness of Ir1 and Ir2 in cellular imaging. Labeled liposomes were then injected intravitreally into rat eyes and imaged successfully with optical coherence tomography and funduscopy. In conclusion, iridium complexes enabled the successful labeling and imaging of liposomes in cells and animals.Peer reviewe

Self-assembly of spherical interpolyelectrolyte complexes from oppositely charged polymers

The formation of inter-polyelectrolyte complexes from the association of oppositely charged polymers in an electrolyte is studied. The charged polymers are linear oppositely charged polyelectrolytes, with possibly a neutral block. This leads to complexes with a charged core, and a more dilute corona of dangling chains, or of loops (flower-like structure). The equilibrium aggregation number of the complexes (number of polycations m+ and polyanions m-) is determined by minimizing the relevant free energy functional, the Coulombic contribution of which is worked out within Poisson-Boltzmann theory. The complexes can be viewed as colloids that are permeable to micro-ionic species, including salt. We find that the complexation process can be highly specific, giving rise to very localized size distribution in composition space (m+,m-).Comment: Soft Matter, in press 201

Diagnostics and prediction of intracranial hypertension on primary computed tomography in patients with severe traumatic brain injury

The objective was to compare the optic nerve sheath diameter measured by CT (ODSN-CT) with the level of compression of the mesencephalic  cisterns and the midline shift in the diagnosis and prediction of intracranial hypertension (ICH) during the first 3 days after brain injury. Materials and methods. We examined 90 patients with TBI, the average age was 34.2 ± 13 years, GCS < 9. All patients had invasive ICP monitoring.  At the time of implantation of the ICP sensor, intracranial hypertension (ICH) was in 11 (12%) patients; later, during the first 3 days, the development of ICH was in 58 (64%) patients. All patients underwent computed tomography of the head at the time of hospitalization: mesencephalic  cisternae was compressed in 57 (63%) and midline shift was observed in 34 (38%) patients, mean value of ONSD-CT was 7.26 ± 0.9 mm, maximum  value of ONSD-CT was 7.34 ± 0.9. We used correlation analysis, logistic regression and ROC-analysis.Results. The level of mesencephalic cisternae compression, mean and maximum value of ONSD-CT correlated with the ICP value measured at the  time of ICP sensor implantation and during the first 72 hours after brain injury (p < 0.05). Midline shift did not correlate with ICP value measured  at the time of sensor implantation and during the first 72 hours after brain injury (p > 0.05). In the diagnosis of ICP > 20 mm Hg at the time of  implantation of the sensor – the average ONSD-CT, AUC 0.902 ± 0.046 (0.812; 0.991), cut-off 7.8 mm with sensitivity and specificity of 82 and  80%, respectively. When predicting ICP > 20 mm Hg in the first 72 hours - the maximum ONSD-CT, AUC 0.815 ± 0.047 (0.724; 0.907), cut-off  7.1 mm with sensitivity and specificity of 85 and 66%, respectively.Conclusions. The ONSD-CT parameter is an independent diagnostic and prognostic criterion of ICH in the first 3 days in patients with severe  TBI. The mean ONSD-CT can be used to diagnose ICH along with such signs of ICP as level of mesencephalic cisterna compression and midline  shift and to make a decision on invasive ICP monitoring. The maximum value of ONSD-CT can be used to assess the probability of ICH in the  first three days after TB

The Role of 5-ALA in Low-Grade Gliomas and the Influence of Antiepileptic Drugs on Intraoperative Fluorescence

Objectives: Intraoperative tumor visualization with 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence is widely applied for improved resection of high-grade gliomas. However, visible fluorescence is present only in a minority of low-grade gliomas (LGGs) according to current literature. Nowadays, antiepileptic drugs (AEDs) are frequently administered to LGG patients prior to surgery. A recent in-vitro study demonstrated that AEDs result in significant reduction of PpIX synthesis in glioma cells. The aim of this study was thus to investigate the role of 5-ALA fluorescence in LGG surgery and the influence of AEDs on visible fluorescence.Patients and Methods: Patients with resection of a newly diagnosed suspected LGG after 5-ALA (25 mg/kg) administration were initially included. During surgery, the presence of visible fluorescence (none, mild, moderate, or bright) within the tumor and intratumoral fluorescence homogeneity (diffuse or focal) were analyzed. Tissue samples from fluorescing and/or non-fluorescing areas within the tumor and/or the assumed tumor border were collected for histopathological analysis (WHO tumor diagnosis, cell density, and proliferation rate). Only patients with diagnosis of LGG after surgery remained in the final study cohort. In each patient, the potential preoperative intake of AEDs was investigated.Results: Altogether, 27 patients with a histopathologically confirmed LGG (14 diffuse astrocytomas, 6 oligodendrogliomas, 4 pilocytic astrocytomas, 2 gemistocytic astrocytomas, and one desmoplastic infantile ganglioglioma) were finally included. Visible fluorescence was detected in 14 (52%) of 27. In terms of fluorescence homogeneity (n = 14), 7 tumors showed diffuse fluorescence, while in 7 gliomas focal fluorescence was noted. Cell density (p = 0.03) and proliferation rate (p = 0.04) was significantly higher in fluorescence-positive than in fluorescence-negative samples. Furthermore, 15 (56%) of 27 patients were taking AEDs before surgery. Of these, 11 patients (73%) showed no visible fluorescence. In contrast, 10 (83%) of 12 patients without prior AEDs intake showed visible fluorescence. Thus, visible fluorescence was significantly more common in patients without AEDs compared to patients with preoperative AED intake (OR = 0,15 (CI 95% 0.012–1.07), p = 0.046).Conclusions: Our study shows a markedly higher rate of visible fluorescence in a series of LGGs compared to current literature. According to our preliminary data, preoperative intake of AEDs seems to reduce the presence of visible fluorescence in such tumors and should thus be taken into account in the clinical setting

Диагностика и прогнозирование внутричерепной гипертензии по данным первичной компьютерной томографии у пострадавших с тяжелой черепно-мозговой травмой

 The objective was to compare the optic nerve sheath diameter measured by CT (ODSN-CT) with the level of compression of the mesencephalic  cisterns and the midline shift in the diagnosis and prediction of intracranial hypertension (ICH) during the first 3 days after brain injury. Materials and methods. We examined 90 patients with TBI, the average age was 34.2 ± 13 years, GCS < 9. All patients had invasive ICP monitoring.  At the time of implantation of the ICP sensor, intracranial hypertension (ICH) was in 11 (12%) patients; later, during the first 3 days, the development of ICH was in 58 (64%) patients. All patients underwent computed tomography of the head at the time of hospitalization: mesencephalic  cisternae was compressed in 57 (63%) and midline shift was observed in 34 (38%) patients, mean value of ONSD-CT was 7.26 ± 0.9 mm, maximum  value of ONSD-CT was 7.34 ± 0.9. We used correlation analysis, logistic regression and ROC-analysis.Results. The level of mesencephalic cisternae compression, mean and maximum value of ONSD-CT correlated with the ICP value measured at the  time of ICP sensor implantation and during the first 72 hours after brain injury (p < 0.05). Midline shift did not correlate with ICP value measured  at the time of sensor implantation and during the first 72 hours after brain injury (p > 0.05). In the diagnosis of ICP > 20 mm Hg at the time of  implantation of the sensor – the average ONSD-CT, AUC 0.902 ± 0.046 (0.812; 0.991), cut-off 7.8 mm with sensitivity and specificity of 82 and  80%, respectively. When predicting ICP > 20 mm Hg in the first 72 hours - the maximum ONSD-CT, AUC 0.815 ± 0.047 (0.724; 0.907), cut-off  7.1 mm with sensitivity and specificity of 85 and 66%, respectively.Conclusions. The ONSD-CT parameter is an independent diagnostic and prognostic criterion of ICH in the first 3 days in patients with severe  TBI. The mean ONSD-CT can be used to diagnose ICH along with such signs of ICP as level of mesencephalic cisterna compression and midline  shift and to make a decision on invasive ICP monitoring. The maximum value of ONSD-CT can be used to assess the probability of ICH in the  first three days after TBI Цель – сравнить диаметр зрительного нерва с оболочками по данным компьютерной томографии (ДЗНО-КТ) со степенью компрессии  мезенцефальных цистерн и смещением срединной линии при диагностике и прогнозировании внутричерепной гипертензии (ВЧГ) в первые  3 суток с момента травмы. Материалы и методы. Обследовали 90 пострадавших с ЧМТ, средний возраст 34,2 ± 13 лет, ШКГ менее 9 баллов. Всем проводили инвазивный мониторинг внутричерепного давления (ВЧД). На момент установки датчика ВЧД ВЧГ диагностирована у 11 (12%) пострадавших,  в дальнейшем течение первых 3 суток развитие ВЧГ регистрировали у 58 (64%) пострадавших. Всем пациентам выполняли КТ головы на  момент госпитализации. При КТ-исследовании компрессия мезенцефальных цистерн была у 57 (63%) и смешение срединной линии – у  34 (38%) пострадавших, среднее значение ДЗНО – 7,26 ± 0,9 мм, максимальное ДЗНО – 7,34 ± 0,9. Использовали корреляционный анализ,  логистическую регрессию и ROC-анализ. Результаты. Степень компрессии мезенцефальных цистерн, среднее и максимальное ДЗНО коррелировали со значением ВЧД, измеренном  на момент постановки датчика и за первые 72 часа мониторинга (p < 0,05). Смещение срединной линии не коррелировало со значением  ВЧД, измеренном на момент постановки датчика и за первые 72 часа мониторинга (p > 0,05). При диагностике ВЧД > 20 мм рт. ст. на момент имплантации датчика – среднее ДЗНО, AUC 0,902 ± 0,046 (0,812; 0,991), cut-off 7,8 мм с чувствительностью и специфичностью 82 и  80% соответственно. При прогнозировании ВЧД > 20 мм рт. ст. в первые 72 часа – максимальное ДЗНО, AUC 0,815 ± 0,047 (0,724; 0,907),  cut-off 7,1 мм с чувствительностью и специфичностью 85 и 66% соответственно. Выводы. Параметр ДЗНО-КТ является самостоятельным диагностическим и прогностическим критерием ВЧГ в первые 3 суток у пострадавших с тяжелой ЧМТ. Среднее значение ДЗНО-КТ можно использовать для диагностики ВЧГ наряду с такими признаками ВЧГ, как  степень компрессии мезенцефальных цистерн и смещение срединной линии, для принятия решения об инвазивном мониторинге ВЧД.  Максимальное значение ДЗНО-КТ можно использовать для оценки вероятности ВЧГ в первые 3 суток после ЧМ

PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO trial

Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial (NCT03147040), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml–1 min–1) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8+ T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials. Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II–III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8+ T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8+ T cells, follicular helper T cells and shorter distances between tumor and CD8+ T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (NCT03815890. Immunobiology of allogeneic stem cell transplantation, transfusion medicine and immunotherapy of hematological disease

PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO trial

Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial (NCT03147040), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml–1 min–1) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8+ T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials

Fiber Optic Sensor Designs and Luminescence-based Methods for the detection of Oxygen and pH measurement

Optical, and especially fiber optic techniques for chemical sensing have become very attractive in recent decades for a wide variety of biomedical and industrial processes and considerable progress in research in this field has been seen, evidenced by the significant number of papers published over several decades, commercial products developed and marketed and which continuing to be produced. This work extends the body of knowledge in the field and focuses on two industrially-important ‘chemical’ measurands: the determination of pH level and oxygen concentration (O2) - both are critically important for a broad range of applications globally, in fields as diverse at the life sciences, environmental monitoring, biomedical research and thus widely across industry. The many different optical platform designs and fabrication methods that have been developed are considered, including those for commercial applications, recognizing the wide range of industrial and scientific uses, and their performance compared. Further, the effect of specific fiber structures on sensor performance, e.g. on sensitivity, response time and long-term stability, and possible applications also has been analyzed. Applications are seen in difficult and ‘niche’ measurement environments to which conventional sensors are often not well suited, taking advantage of their lightweight nature, ease of miniaturization, potential to be multiplexed and low cost. Through a discussion of representative techniques that have reached commercial development, a comprehensive and state-of-the-art view of this exciting and important field is possible