Single-drive electro-optic frequency comb source on a photonic-wire-bonded thin-film lithium niobate platform.

Stable pulse and flat-top frequency comb generation are an indispensable component of many photonic applications, from ranging to communications. Lithium niobate on insulator is an excellent electro-optic (EO) platform, exhibiting high modulation efficiency and low optical loss, making it a fitting candidate for pulse generation through electro-optic modulation of continuous-wave (CW) light, a commonly utilized method for generating ultrashort pulses. Here, we demonstrate an on-chip electro-optic comb generation module on thin-film lithium niobate (TFLN) consisting of a Mach-Zehnder interferometer (MZI) amplitude modulator (AM) and a cascaded phase modulator (PM) system driven by a single-electrode drive. We show that when operated in the correct regime, the lithium niobate chips can generate frequency combs with excellent spectral power flatness. In addition, we optically package one of the pulse generator chips via photonic wire bonding. The pulses generated by the photonic-wire-bonded device are compressed to 840 fs pulse duration using an optical fiber and show extremely stable operation.

Expression of inducible nitric oxide synthase, nitrotyrosine, eosinophilic peroxidase, eotaxin-3, and galectin-3 in patients with gastroesophageal reflux disease, eosinophilic esophagitis, and in healthy controls: a semiquantitative image analysis of 3,3'-diaminobenzidine-stained esophageal biopsies.

Eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD) share many histopathological features; therefore, markers for differentiation are of diagnostic interest and may add to the understanding of the underlying mechanisms. The nitrergic system is upregulated in GERD and probably also in EoE. Esophageal biopsies of patients with EoE (n = 20), GERD (n = 20), and healthy volunteers (HVs) (n = 15) were exposed to antibodies against inducible nitric oxide synthase (iNOS), nitrotyrosine, eosinophilic peroxidase, eotaxin-3, and galectin-3. The stained object glasses were randomized, digitized, and blindly analyzed regarding the expression of DAB (3,3'-diaminobenzidine) by a protocol developed in QuPath software. A statistically significant overexpression of iNOS was observed in patients with any of the two inflammatory diseases compared with that in HVs. Eotaxin-3 could differentiate HVs versus inflammatory states. Gastroesophageal reflux patients displayed the highest levels of nitrotyrosine. Neither iNOS nor nitrotyrosine alone were able to differentiate between the two diseases. For that purpose, eosinophil peroxidase was a better candidate, as the mean levels increased stepwise from HVs via GERD to EoE. iNOS and nitrotyrosine are significantly overexpressed in patients with EoE and GERD compared with healthy controls, but only eosinophil peroxidase could differentiate the two types of esophagitis. The implications of the finding of the highest levels of nitrotyrosine among gastroesophageal reflux patients are discussed.

A randomized study comparing the nutritional effects of radiotherapy with cetuximab versus cisplatin in patients with advanced head and neck cancer.

BACKGROUND: Head and neck cancer (HNC) patients have a high risk of developing malnutrition. This randomized study aimed to compare the effect of weekly cisplatin or cetuximab combined with radiotherapy on weight loss at 3 months after treatment was started. Secondary outcomes were the prevalence of malnutrition using the Global Leadership Initiative on Malnutrition (GLIM) criteria, feeding tube dependence and health related quality of life from a nutritional perspective. METHODS: Patients from the ARTSCAN III study with advanced HNC were assessed for weight, body composition, enteral tube dependence and selected quality-of-life scores (EORTC QLQ-C30 and QLQ-H&N35) at diagnosis and 6 weeks 3, 6 and 12 months after treatment initiation. RESULTS: Of the 80 patients, 38 and 42 were randomized to receive cetuximab and cisplatin treatment, respectively. There was no significant difference in weight loss at 3 months between the two study groups. However, the cetuximab group had significantly less weight loss, fewer enteral feeding tubes and better physical functioning at the end of treatment but more pain-related problems 3 months after treatment initiation. No differences between the groups were found at 6 and 12 months. The prevalence of malnutrition was not significantly different at any time point. CONCLUSION: The hypothesized benefit of concomitant treatment with cetuximab over cisplatin regarding the prevalence of malnutrition was not supported by this study.

Extracellular distribution of galectin-10 in the esophageal mucosa of patients with eosinophilic esophagitis.

Eosinophilic esophagitis is a T-cell-driven allergic condition hallmarked by eosinophil infiltration of the esophagus. Eosinophils exposed to proliferating T cells release galectin-10 and have T-cell suppressive function in vitro. The aims of this study were to evaluate if eosinophils co-localize with T cells and release galectin-10 in the esophagus of patients with eosinophilic esophagitis. Esophageal biopsies from 20 patients with eosinophilic esophagitis were stained for major basic protein, galectin-10, CD4, CD8, CD16, and CD81 and analyzed by immunofluorescence confocal microscopy before and after topical corticosteroid treatment. CD4+ T-cell numbers decreased in the esophageal mucosa of responders to treatment but not in the non-responders. Suppressive (CD16+) eosinophils were present in the esophageal mucosa of patients with active disease and decreased after successful treatment. Unexpectedly, eosinophils and T cells were not in direct contact with each other. Instead, the esophageal eosinophils released large amounts of galectin-10-containing extracellular vesicles and featured cytoplasmic projections that contained galectin-10, both of which disappeared from the esophagus of the responders but remained in the non-responders. To conclude, the presence of CD16+ eosinophils together with the massive release of galectin-10-containing extracellular vesicles in the esophageal mucosa might indicate that eosinophils exert T-cell suppression in eosinophilic esophagitis.

Fatigue in Long-Term Head and Neck Cancer Survivors From Diagnosis Until Five Years After Treatment.

OBJECTIVES: Fatigue due to cancer is a challenging symptom that might be long-lasting after cancer treatment. The aim of this study was to follow the development of fatigue among head and neck cancer (HNC) patients prospectively and longitudinally and to analyze predictors for acute and chronic fatigue. METHODS: HNC patients treated with curative intent were included at diagnosis and completed the following questionnaires multiple times, up to 5 years after treatment: the EORTC QLQ-FA12 for fatigue, EORTC QLQ-C30, and HNC-specific EORTC QLQ-H&N35 together with an anxiety and depression questionnaire. Predictors of fatigue were evaluated at 3 months and 5 years after treatment. RESULTS: Of the 311 study participants, 74% responded at the 5-year follow-up. Physical fatigue was significantly worse 3 months after treatment, while emotional and cognitive fatigue were the worst at diagnosis and at 3 months. All fatigue domains were significantly better after 1 year, and the fatigue scores remained stable from 1 until 5 years after treatment. Three months after chemoradiotherapy, physical fatigue was more significant, but no long-term differences due to treatment modalities were found. Depression and anxiety were predictors for chronic emotional fatigue, and local HN pain and swallowing problems were predictors for chronic physical fatigue. Better global quality of life at diagnosis was associated with less physical and emotional fatigue. CONCLUSION: Fatigue was worst in the short term for HNC patients and improved after 1 year, and long-term fatigue remained stable up to 5 years after treatment. A few predictors for chronic fatigue were found. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2211-2221, 2023.

Integrated femtosecond pulse generator on thin-film lithium niobate.

Integrated femtosecond pulse and frequency comb sources are critical components for a wide range of applications, including optical atomic clocks1, microwave photonics2, spectroscopy3, optical wave synthesis4, frequency conversion5, communications6, lidar7, optical computing8 and astronomy9. The leading approaches for on-chip pulse generation rely on mode-locking inside microresonators with either third-order nonlinearity10 or with semiconductor gain11,12. These approaches, however, are limited in noise performance, wavelength and repetition rate tunability 10,13. Alternatively, subpicosecond pulses can be synthesized without mode-locking, by modulating a continuous-wave single-frequency laser using electro-optic modulators1,14-17. Here we demonstrate a chip-scale femtosecond pulse source implemented on an integrated lithium niobate photonic platform18, using cascaded low-loss electro-optic amplitude and phase modulators and chirped Bragg grating, forming a time-lens system19. The device is driven by a continuous-wave distributed feedback laser chip and controlled by a single continuous-wave microwave source without the need for any stabilization or locking. We measure femtosecond pulse trains (520-femtosecond duration) with a 30-gigahertz repetition rate, flat-top optical spectra with a 10-decibel optical bandwidth of 12.6 nanometres, individual comb-line powers above 0.1 milliwatts, and pulse energies of 0.54 picojoules. Our results represent a tunable, robust and low-cost integrated pulsed light source with continuous-wave-to-pulse conversion efficiencies an order of magnitude higher than those achieved with previous integrated sources. Our pulse generator may find applications in fields such as ultrafast optical measurement19,20 or networks of distributed quantum computers21,22.

A Late Paleocene age for Greenland's Hiawatha impact structure.

The ~31-km-wide Hiawatha structure, located beneath Hiawatha Glacier in northwestern Greenland, has been proposed as an impact structure that may have formed after the Pleistocene inception of the Greenland Ice Sheet. To date the structure, we conducted 40Ar/39Ar analyses on glaciofluvial sand and U-Pb analyses on zircon separated from glaciofluvial pebbles of impact melt rock, all sampled immediately downstream of Hiawatha Glacier. Unshocked zircon in the impact melt rocks dates to ~1915 million years (Ma), consistent with felsic intrusions found in local bedrock. The 40Ar/39Ar data indicate Late Paleocene resetting and shocked zircon dates to 57.99 ± 0.54 Ma, which we interpret as the impact age. Consequently, the Hiawatha impact structure far predates Pleistocene glaciation and is unrelated to either the Paleocene-Eocene Thermal Maximum or flood basalt volcanism in east Greenland. However, it was contemporaneous with the Paleocene Carbon Isotope Maximum, although the impact's exact paleoenvironmental and climatic significance awaits further investigation.

The effect of age on health-related quality of life for head and neck cancer patients up to 1 year after curative treatment.

OBJECTIVES: The aim was to evaluate the effect of age on health-related quality of life (HRQOL) for patients with head and neck cancer (HNC), treated with curative intent, in the Western healthcare region of Sweden. MATERIALS AND METHODS: In this prospective observational study, 311 HNC patients completed quality of life questionnaires for cancer (EORTC QLQ-C30 and EORTC QLQ-H&N35) and for older patients with cancer (EORT QLQ-ELD14) at diagnosis and 3, 6, and 12 months after start of treatment. Mean scores for patients ≥70 years old were compared to younger patients (50 to 69 years old) to assess differences in HRQOL. RESULTS: Of the 311 study participants, 105 patients were ≥70 years old (median age 76.7), of which 32 were ≥80 years of age. Most HRQOL scores were equal or better for older adult patients at 3 months after treatment, but physical function was better for younger adult patients up to 12 months after treatment. At 6 months the HRQOL was similar (older patients had less appetite loss and financial difficulties), while the oldest patients (≥80 years) had worse fatigue, role function, and feeling ill at 12 months. For the EORTC-ELD-14 questionnaire, older patients scored better for worries at diagnosis and reported more difficulties in maintaining purpose at 12 months after treatment. CONCLUSION: When curative treatment is administered, older adult patients with HNC have similar or even better HRQOL compared to younger adult patients, except for physical function, during the first year.

Photonic integrated circuit based compressive sensing radio frequency receiver using waveguide speckle.

A photonic integrated circuit (PIC) comprised of an 11 cm long multimode speckle waveguide, a 1 × 32 splitter, and a linear grating coupler array is fabricated and utilized to receive 2 GHz of radio-frequency (RF) signal bandwidth from 2.5 to 4.5 GHz using compressive sensing (CS). Incoming RF signals are modulated onto chirped optical pulses which are input to the multimode waveguide. The multimode waveguide produces the random projections needed for CS via optical speckle. The time-varying phase and amplitude of two test RF signals between 2.5 and 4.5 GHz are successfully recovered using the standard penalized l1-norm method. The PIC reduces the speckle mixer footprint compared with the previously demonstrated fiber system. Two new PIC structures, the "waveguide bus trombone flare" and the "matched 90 degree bus bend" are developed to support precise analog signal routing. The use of a passive PIC serves as an initial critical step towards the miniaturization of a compressive sensing RF receiver.

Topically applied mometasone furoate improves dysphagia in adult eosinophilic esophagitis - results from a double-blind, randomized, placebo-controlled trial.

OBJECTIVES: Topical corticosteroids are considered a cornerstone in the treatment of patients with eosinophilic esophagitis. The aim of this study was to evaluate the benefit of using mometasone furoate spray versus placebo on dysphagia and health-related quality of life in these patients. MATERIAL AND METHODS: Consecutive, newly diagnosed adult patients with eosinophilic esophagitis were randomized and treated with either 200 micrograms of orally administered topical mometasone furoate or placebo 4 times daily for 8 weeks. Symptoms and quality of life were evaluated using questionnaires including the Watson Dysphagia Scale, the European Organization for Research and Treatment of Cancer Quality of Life-Oesophageal Module 18 and the Short Form-36 before and after treatment. RESULTS: In the intention-to-treat analysis (n = 36) the Watson Dysphagia Scale score after mometasone treatment was reduced by 6.5 (median, p < .01) compared with 0 (median, ns) in the placebo group. The benefit of mometasone over placebo was significant (p < .05). In the per-protocol analysis (n = 33) the Watson Dysphagia Scale score was reduced by 5 (median, p = .01) after mometasone treatment compared with 0 (median, ns) in the placebo group. The advantage of mometasone over the placebo was significant (p < .05). The benefit of using mometasoneas evaluated by the two quality of life questionnaires was, however, insignificant. CONCLUSIONS: Our finding suggests that in adult patients with eosinophilic esophagitis, topical mometasone furoate exerts a beneficial effect compared with placebo regarding the main symptom, i.e., dysphagia. A corresponding benefit could not be verified regarding the various quality of life measurements. CLINICAL TRIAL REGISTRATION: Mometasone-furoate for Treatment of Eosinophilic Esophagitis - a Randomized Placebo Controlled Study ClinicalTrials.gov Identifier (NCT02113267).

Patient-Reported Outcomes and Blood-Based Parameters Identify Response to Treatment in Eosinophilic Esophagitis.

BACKGROUND: Noninvasive methods to assess treatment response in eosinophilic esophagitis are needed. AIMS: Our aim was to determine whether a blood-based biomarker panel centered on immune parameters could identify histologic response to treatment in eosinophilic esophagitis patients. METHODS: A pilot study involving adult patients with active eosinophilic esophagitis recruited at two Ear, Nose, Throat clinics in Sweden was designed. The patients (n = 20) donated blood and esophageal biopsies and filled in three questionnaires before and after a 2-month course of topical corticosteroids. Blood samples were analyzed for absolute levels of granulocytes and T cells and the fractions of eosinophils expressing 10 different surface markers by flow cytometry. All data were analyzed by multivariate methods of pattern recognition. RESULTS: Multivariate modeling revealed that a combination of 13 immune parameters and 10 patient-reported outcome scores were required to create a model capable of separating responders (n = 15) from non-responders (n = 5). Questions regarding symptoms of esophageal dysfunction and capacity to eat certain foods from two of the questionnaires were discriminatory in the multivariate model, as were absolute counts of T cells, eosinophils, and eosinophil expression of activation markers and cell adhesion molecules. CONCLUSIONS: A combination of blood-based immune parameters and directed questions may prove helpful to monitor response to treatment, perhaps reducing the need for repeat endoscopies in eosinophilic esophagitis patients in the future.

Relative frequencies of symptoms and risk factors among patients with chronic rhinosinusitis with nasal polyps using a case-control study.

OBJECTIVES: The aim of this study was to investigate the relative frequency of important symptoms of chronic rhinosinusitis with nasal polyps (CRSwNP), the link between CRSwNP and the lower airways and the importance of smoking in CRSwNP. METHOD: Three hundred and sixty-eight patients with CRSwNP and 1349 controls were recruited to the study and underwent a structured interview about symptoms from the upper and lower airways, and about smoking habits. Furthermore, all participants were clinically examined using nasal endoscopy. RESULTS: Due to interactions between the outcome variables, a multiple logistic regression model was fitted to the data. Nasal secretions, nasal blockage and impaired sense of smell were symptoms associated with CRSwNP. Furthermore, male gender, increasing age and asthma were also associated with the disease. Current smoking was less frequent among patients with CRSwNP. CONCLUSION: By comparing symptoms and risk factors of patients with CRSwNP with those of a large population-based control group and testing them in a multiple logistic regression model, we have been able to generate data that address key research interests in CRSwNP.

Impact on quality of life of IMRT versus 3-D conformal radiation therapy in head and neck cancer patients: A case control study.

OBJECTIVE: The purpose of this study was to prospectively and longitudinally compare the health-related quality of life (HRQOL) outcomes between head and neck (HN) cancer patients treated with parotid-sparing intensity modulated radiation therapy (IMRT) and patients treated with 3-dimensional conventional radiation therapy (3D-CRT). METHODS AND MATERIALS: Before and up to 12 months after treatment, HRQOL was recorded in patients with HN cancer who were referred to the Department of Oncology at Sahlgrenska University Hospital for curative IMRT. The study group's HRQOL was compared with a matched group of patients from previous descriptive HRQOL studies treated with 3D-CRT. Both groups' HRQOL was measured by the European Organization for Research and Treatment for Cancer QLQ-C30 and European Organization for Research and Treatment for Cancer QLQ-HN35 at 6 time points in the first year after diagnosis. RESULTS: Two hundred and seven patients were included, 111 treated with IMRT and 96 matched controls treated with 3D-CRT. Both groups' HRQOL deteriorated during and after treatment. Just after treatment, worse HRQOL scores were observed in the IMRT group regarding insomnia (38 vs 27; P = .032), appetite loss (64 vs 50; P = .019), senses (54 vs 41; P = .017), and coughing (39 vs 26, P = .009). At 12 months, however, significantly better HRQOL scores were observed in the IMRT group regarding problems with dry mouth (72 vs 62; P = .018), pain (28 vs 20; P = .018), sexuality (37 vs 23; P = .016), social contacts (10 vs 6; P = .026), cognitive functioning (79 vs 87; P = .0057), and financial difficulties (12 vs 20; P = .0019). CONCLUSIONS: This study further supports the hypothesis that the introduction of IMRT has improved the long-term quality of life of HN cancer patients who have been treated with radiation therapy, but might cause more acute side effects. Longer follow-up is needed to study late complications.

Prognostic factors for head and neck cancer of unknown primary including the impact of human papilloma virus infection.

BACKGROUND: Head and neck cancer of unknown primary (HNCUP) is rare and prospective studies are lacking. The impact of different prognostic factors such as age and N stage is not completely known, the optimal treatment is not yet established, and the reported survival rates vary. In the last decade, human papilloma virus (HPV) has been identified as a common cause of and important prognostic factor in oropharyngeal cancer, and there is now growing interest in the importance of HPV for HNCUP. The aim of the present study on curatively treated HNCUP was to investigate the prognostic importance of different factors, including HPV status, treatment, and overall survival. METHODS: A search for HNCUP was performed in the Swedish Cancer Registry, Western health district, between the years 1992-2009. The medical records were reviewed, and only patients with squamous cell carcinoma or undifferentiated carcinoma treated with curative intent were included. The tumor specimens were retrospectively analyzed for HPV with p16 immunostaining. RESULTS: Sixty-eight patients were included. The mean age was 59 years. The majority were males, and had N2 tumors. Sixty-nine percent of the tumors were HPV positive using p16 staining. Patients who were older than 70 years, patients with N3-stage tumors, and patients with tumors that were p16 negative had a significantly worse prognosis. The overall 5-year survival rate for patients with p16-positive tumors was 88% vs 61% for p16-negative tumors. Treatment with neck dissection and postoperative radiation or (chemo) radiation had 81 and 88% 5-year survival rates, respectively. The overall and disease-free 5-year survival rates for all patients in the study were 82 and 74%. CONCLUSIONS: Curatively treated HNCUP had good survival. HPV infection was common. Independent prognostic factors for survival were age over 70 years, HPV status and N3 stage. We recommend that HPV analysis should be performed routinely for HNCUP. Treatment with neck dissection and postoperative radiation or (chemo) radiation showed similar survival rates.

Towards chip-scale optical frequency synthesis based on optical heterodyne phase-locked loop.

An integrated heterodyne optical phase-locked loop was designed and demonstrated with an indium phosphide based photonic integrated circuit and commercial off-the-shelf electronic components. As an input reference, a stable microresonator-based optical frequency comb with a 50-dB span of 25 nm (~3 THz) around 1550 nm, having a spacing of ~26 GHz, was used. A widely-tunable on-chip sampled-grating distributed-Bragg-reflector laser is offset locked across multiple comb lines. An arbitrary frequency synthesis between the comb lines is demonstrated by tuning the RF offset source, and better than 100Hz tuning resolution with ± 5 Hz accuracy is obtained. Frequency switching of the on-chip laser to a point more than two dozen comb lines away (~5.6 nm) and simultaneous locking to the corresponding nearest comb line is also achieved in a time ~200 ns. A low residual phase noise of the optical phase-locking system is successfully achieved, as experimentally verified by the value of -80 dBc/Hz at an offset of as low as 200 Hz.

Effect of prophylactic percutaneous endoscopic gastrostomy tube on swallowing in advanced head and neck cancer: A randomized controlled study.

BACKGROUND: Dysphagia is common in head and neck cancer. A percutaneous endoscopic gastrostomy (PEG) tube is used to facilitate nutrition; however, some retrospective studies have indicated that the PEG tube causes dysphagia. METHODS: A randomized study of patients with head and neck cancer was conducted with up to 10 years of follow-up. Patients were randomized to either the prophylactic PEG tube group (study group) or the common clinical nutritional support group (control group). At each follow-up, a dietician assessed the oral intake, noted the patients' weight, and if the patients used a PEG tube. Dysphagia was also assessed by the quality of life questionnaire, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Head and Neck 35-questions (EORTC-QLQ-H&N35). RESULTS: One hundred thirty-four patients were included in this study. There was no significant difference in swallowing function between the groups after 12 months, 24 months, and 8 years based on the EORTC-QLQ-H&N35, the oral intake scale, tube dependence, esophageal intervention, weight, body mass index (BMI), and overall survival. CONCLUSION: A prophylactic PEG tube can be used without an increased risk of long-term dysphagia in patients with head and neck cancer. © 2017 Wiley Periodicals, Inc. Head Neck 39: 908-915, 2017.

Nanoscale Structure and Spectroscopic Probing of Aß1-40 Fibril Bundle Formation.

Amyloid plaques composed of fibrillar Amyloid-ß (Aß) are hallmarks of Alzheimer's disease. However, Aß fibrils are morphologically heterogeneous. Conformation sensitive luminescent conjugated oligothiophenes (LCOs) are versatile tools for monitoring such fibril polymorphism in vivo and in vitro. Biophysical methods applied on in vitro generated Aß fibrils, stained with LCOs with different binding and fluorescence properties, can be used to characterize the Aß fibrillation in depth, far beyond that possible for in vivo generated amyloid plaques. In this study, in vitro fibrillation of the Aß1-40 peptide was monitored by time-lapse transmission electron microscopy, LCO fluorescence, and atomic force microscopy. Differences in the LCO binding in combination with nanoscale imaging revealed that spectral variation correlated with fibrils transforming from solitary filaments (Ø~2.5 nm) into higher order bundled structures (Ø~5 nm). These detailed in vitro experiments can be used to derive data that reflects the heterogeneity of in vivo generated Aß plaques observed by LCO fluorescence. Our work provides new structural basis for targeted drug design and molecular probe development for amyloid imaging.

What Happens With Untreated Nasal Polyps Over Time? A 13-Year Prospective Study.

OBJECTIVES: Nasal polyps are often seen in ENT practice, but little is known about the pathogenesis and the natural development. Our objective was to follow individuals with untreated nasal polyps prospectively, in terms of polyp size, symptoms, and respiratory function. METHODS: Thirty-three individuals, aged 27 to 87 years, with untreated nasal polyps were identified in a population-based study. Peak nasal inspiratory flow, olfactory function, and size of the nasal polyps were examined. Respiratory symptoms were also registered. Follow-up examinations were performed after 6 and 13 years, with change between visits analyzed. RESULTS: Over time, polyp size as well as occurrence of unilateral or bilateral polyps varied without an obvious pattern, with no consistent trends in respiratory function or symptoms. Twenty-one individuals (64%) were still untreated at the 6-year follow-up, and 12 (36%) remained untreated during the whole 13-year follow-up. Dropouts were due mainly to death. Seven individuals (21%) started treatment during the follow-up and had larger polyps and more subjective respiratory symptoms at baseline compared to the untreated group. CONCLUSION: Nasal polyps found occasionally are often part of a chronic entity but do not necessarily evolve into a more serious condition over time. Treatment should therefore be based on the patients' subjective problems.

(11)C and (18)F Radiolabeling of Tetra- and Pentathiophenes as PET-Ligands for Amyloid Protein Aggregates.

Three oligothiophenes were evaluated as PET ligands for the study of local and systemic amyloidosis ex vivo using tissue from patients with amyloid deposits and in vivo using healthy animals and PET-CT. The ex vivo binding studies revealed that all three labeled compounds bound specifically to human amyloid deposits. Specific binding was found in the heart, kidney, liver, and spleen. To verify the specificity of the oligothiophenes toward amyloid deposits, tissue sections with amyloid pathology were stained using the fluorescence exhibited by the compounds and evaluated with multiphoton microscopy. Furthermore, a in vivo monkey PET-CT study showed very low uptake in the brain, pancreas, and heart of the healthy animal indicating low nonspecific binding to healthy tissue. The biological evaluations indicated that this is a promising group of compounds for the visualization of systemic and localized amyloidosis.

Real-time optotracing of curli and cellulose in live Salmonella biofilms using luminescent oligothiophenes.

Extracellular matrix (ECM) is the protein- and polysaccharide-rich backbone of bacterial biofilms that provides a defensive barrier in clinical, environmental and industrial settings. Understanding the dynamics of biofilm formation in native environments has been hindered by a lack of research tools. Here we report a method for simultaneous, real-time, in situ detection and differentiation of the Salmonella ECM components curli and cellulose, using non-toxic, luminescent conjugated oligothiophenes (LCOs). These flexible conjugated polymers emit a conformation-dependent fluorescence spectrum, which we use to kinetically define extracellular appearance of curli fibres and cellulose polysaccharides during bacterial growth. The scope of this technique is demonstrated by defining biofilm morphotypes of Salmonella enterica serovars Enteritidis and Typhimurium, and their isogenic mutants in liquid culture and on solid media, and by visualising the ECM components in native biofilms. Our reported use of LCOs across a number of platforms, including intracellular cellulose production in eukaryotic cells and in infected tissues, demonstrates the versatility of this optotracing technology, and its ability to redefine biofilm research.