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Supplementary Figure S1. CONSORT flow diagram for patient selection

Patient characteristics

Ipilimumab is effective for patients with melanoma, but not for those with less immunogenic tumors. We report a phase II trial of ipilimumab with concurrent or sequential stereotactic ablative radiotherapy to metastatic lesions in the liver or lung (NCT02239900). Ipilimumab (every 3 weeks for 4 doses) was given with radiotherapy begun during the first dose (concurrent) or 1 week after the second dose (sequential) and delivered as 50 Gy in 4 fractions or 60 Gy in 10 fractions to metastatic liver or lung lesions. In total, 106 patients received ≥1 cycle of ipilimumab with radiation. Median follow-up was 10.5 months. Median progression-free survival time was 2.9 months (95% confidence interval, 2.45–3.40), and median overall survival time was not reached. Rates of clinical benefit of nonirradiated tumor volume were 26% overall, 28% for sequential versus 20% for concurrent therapy (P = 0.250), and 31% for lung versus 14% for liver metastases (P = 0.061). The sequential lung group had the highest rate of clinical benefit at 42%. There were no differences in treatment-related adverse events between groups. Exploratory analysis of nontargeted lesions revealed that lesions receiving low-dose radiation were more likely to respond than those that received no radiation (31% vs. 5%, P = 0.0091). This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to further investigation of combined-modality therapy for metastatic cancers.

We recently published in GUT the outcomes of acute pancreatitis (AP) and coexisting SARS-CoV-2 infection.1 A number of patients who were SARS-CoV-2 positive had AP of unknown aetiology (25%) speculating SARS-CoV-2 as a cause for AP similar to other viruses.2 However, most patients did not complete investigations to exclude other causes of AP. In addition, SARS-CoV-2 infection may cause aberrant glycometabolic control,3 however it is unknown if this increases the risk of long-term diabetes mellitus (DM). The follow-up data were collected 12 months from the date of recruitment for 1476 patients (118 patients who were SARS-CoV-2 positive and 1358 patients who were negative) to establish an aetiology for AP and development of DM. Among the 118 patients who were SARS-CoV-2 positive, 35 patients had idiopathic or unknown aetiology AP. Sixteen patients underwent either MRCP (n=13) or EUS (n=4) and the remaining patients underwent biochemical investigations to exclude other causes of AP. The final aetiology of AP was available for 83 (70.3%) patients and included gallstones (56, 47.4%), alcohol (19, 16.1%), post ERCP (2, 1.7%) and other (6, 5.1%). Overall, 23 patients had a change of aetiology, and in 35 (29.7%) patients AP was considered idiopathic. Patients who were SARS-CoV-2 positive were more likely to have idiopathic AP (34.7% vs 13.9%, p

Avocado by-products present a waste issue for cold-pressed avocado oil processors in New Zealand. The avocado seed contains many extractable compounds that are beneficial to health. This work aims to evaluate the effects of roasting fermented avocado seed to produce a food ingredient with beneficial antioxidant and anticancer properties. Avocado seeds were subjected to natural fermentation and inoculated fermentation with either Lactobacillus plantarum or kefir. The fermented samples were evaluated in terms of total plate count values of lactic acid bacteria acetic acid bacteria and yeasts. The number of microorganisms increased significantly (p < 0.001) over the 7 days of fermentation for all samples. Fermentation with L. plantarum resulted in significantly (p < 0.05) higher total phenolic content (TPC) and antioxidant activities compared to kefir and naturally fermented samples. The fermented avocado seeds were further subjected to roasting to yield a shelf-stable dried powder. Roasted samples fermented by L. plantarum had significantly (p < 0.001) higher total polyphenolic content and antioxidant capacity (CUPRAC and Ferric Reducing Antioxidant Power assays) compared to kefir and naturally fermented samples. The avocado seed powder showed the best inhibition effect on Hep G2 followed by the MDA-MB-231 and MCF-7 cancer cell lines. The roasting conditions for optimal antioxidant and anticancer activities were determined to be at 127°C for 24.7 min. This study demonstrated that fermentation of avocado seeds in combination with roasting yielded a powder with good antioxidant and anticancer activities, which can potentially be incorporated into food for added health benefits.

Due to the risk of postoperative hypotension (PH), invasive monitoring is recommended for patients who undergo adrenalectomy for phaeochromocytoma. Due to high costs and limited availability of intensive care, our aim was to identify patients at low risk of PH who may not require invasive monitoring.Data for patients who underwent adrenalectomy for phaeochromocytoma between 2012 and 2020 were retrospectively collected by nine UK centres, including patient demographics, intraoperative and postoperative haemodynamic parameters. Independent risk factors for PH were analysed and used to develop a clinical risk score.PH developed in 118 of 430 (27.4%) patients. On univariable analysis, female sex (p = 0.007), tumour size (p 0.001), preoperative catecholamine level (p 0.001), open surgery (p 0.001) and epidural analgesia (p = 0.006) were identified as risk factors for PH. On multivariable analysis, female sex (OR 1.85, CIThe derived risk score allows stratification of patients at risk of postoperative hypotension after adrenalectomy for phaeochromocytoma. Postoperatively, low risk patients may be managed on a surgical ward, whilst high risk patients should undergo invasive monitoring.

Token acts of online support, also known as clicktivism, have received much criticism in recent years for suppressing subsequent prosocial behavior. However, whether, when, and why individuals perform less prosocial behavior following these acts remains relatively unknown. To address these questions, we designed a lab experiment in which participants ( N = 193) were randomly assigned to engage in public, private, or no act of clicktivism. Consistent with moral self-licensing theory, those who signed an online petition were less likely to donate than those who did not sign any petition. Public clicktivism (compared to private clicktivism) increased donation intentions among those with high impression management tendencies (i.e. high self-monitors). Concerns about one’s moral self-image partially mediated these effects. Theoretical and practical implications of these findings are discussed.

Ipilimumab is effective for patients with melanoma, but not for those with less immunogenic tumors. We report a phase II trial of ipilimumab with concurrent or sequential stereotactic ablative radiotherapy to metastatic lesions in the liver or lung (NCT02239900). Ipilimumab (every 3 weeks for 4 doses) was given with radiotherapy begun during the first dose (concurrent) or 1 week after the second dose (sequential) and delivered as 50 Gy in 4 fractions or 60 Gy in 10 fractions to metastatic liver or lung lesions. In total, 106 patients received ≥1 cycle of ipilimumab with radiation. Median follow-up was 10.5 months. Median progression-free survival time was 2.9 months (95% confidence interval, 2.45–3.40), and median overall survival time was not reached. Rates of clinical benefit of nonirradiated tumor volume were 26% overall, 28% for sequential versus 20% for concurrent therapy (P = 0.250), and 31% for lung versus 14% for liver metastases (P = 0.061). The sequential lung group had the highest rate of clinical benefit at 42%. There were no differences in treatment-related adverse events between groups. Exploratory analysis of nontargeted lesions revealed that lesions receiving low-dose radiation were more likely to respond than those that received no radiation (31% vs. 5%, P = 0.0091). This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to further investigation of combined-modality therapy for metastatic cancers.

Penetrating facial trauma can present without a compromised airway, but some cases present major challenges with disruption...

Molluscan extracts confer a wide range of health promoting properties, one of them is cytotoxicity. Extraction and processing can affect the efficacy and properties of bioactive molecules. New Zealand (NZ) surf clams have never been thoroughly studied for bioactives until recently. However, the effect of cold and heat extraction procedure on biochemical composition and cytotoxic activities of NZ surf clam remains unanswered. The objective is to compare the effects on cytotoxicity of three NZ surf clams (Diamond shell, Crassula aequilatera; Storm shell, Mactra murchisoni; and Deepwater Tua tua, Paphies donacina) extracts via cold or heat process across cancer cell lines to find out which process can preserve bioactivity better. Fractions of extracts prepared via cold or heat procedures were tested for cell growth inhibition, apoptosis induction and cell cycle arrest in seven cancer cell lines. Apoptosis was induced through all cell lines, as further evidenced in Caspase-3/7 activities. Cell cycle arrest was focused on G2/M- and S- phases. Petroleum ether and ethyl acetate fractions, with the greatest bioactivity in this study, are rich in lipids and proteins, indicating likely bioactive sources. Cold preparation was responsible for the lowest cancer cell viability and induced greater apoptosis. Cold process retained better bioactivity/cytotoxicity than that of heat-processed extracts. This information may guide future health/nutraceutical clam product development., Food science, Food technology, Surf clam, Drying, Cytotoxicity, Storm shell, Tua tua, Dimond shell, Crassula aequilatera, Mactra murchisoni, Paphies donacina, New Zealand.

Peptides can serve as versatile therapeutics with a highly modular structure and tunable biophysical properties. In particular, the efficacy of peptide antibiotics against drug-resistant pathogens is of great promise, as few new classes of antibiotics are being developed to overcome the ever-increasing bacterial resistance to contemporary drugs. This work reports biophysical and antimicrobial studies of a designed library of ultrashort peptides that self-assemble into hydrogels at concentrations as low as 0.5% w/v in buffered saline, as confirmed by rheology. The hydrogels are constituted by β-sheet-rich nanofibril networks, as determined by biophysical techniques including spectroscopy (attenuated total reflectance Fourier transform infrared spectroscopy and Congo red binding assay), short- and wide-angle X-ray scattering, and electron microscopy. Both peptide solutions and self-assembled hydrogels show potent antimicrobial activity against S. aureus and Pseudomonas aeruginosa by membrane lysis. These peptides also displayed selectivity toward bacterial cells over human dermal fibroblasts in vitro, as determined from Live/Dead, scanning electron microscopy, and coculture assays. This work reports an antimicrobial self-assembling motif of only three residues comprising an aromatically acylated cationic d-Dab/Lys amino acid, a second cationic residue, and naphthylalanine that heavily influences the self-assembly of these peptides into hydrogels. The variations in the antimicrobial activity and self-assembly properties between analogues may have implications in future studies on the correlation between self-assembly and biological activity in ultrashort peptides.

Breaches in the skin barrier initiate an inflammatory immune response that is critical for successful wound healing. Innate lymphoid cells (ILCs) are a recently identified population of immune cells that reside at epithelial barrier surfaces such as the skin, lung and gut and promote pro-inflammatory or epithelial repair functions following exposure to allergens, pathogens or chemical irritants. However, the potential role of ILCs in regulating cutaneous wound healing remains undefined. Here, we demonstrate that cutaneous injury promotes an IL-33-dependent group 2 ILC (ILC2) response and that abrogation of this response impairs re-epithelialization and efficient wound closure. Additionally, we provide evidence suggesting that an analogous ILC2 response is operational in acute wounds of human skin. Together, these results indicate that IL-33-responsive ILC2s are an important link between the cutaneous epithelium and the immune system, acting to promote the restoration of skin integrity following injury.

Novel antibiotic treatments are in increasing demand to tackle life-threatening infections from bacterial pathogens. In this study, we report the use of a potent battacin lipopeptide as an antimicrobial gel to inhibit planktonic and mature biofilms of S. aureus and P. aeruginosa. The antimicrobial gels were made by covalently linking the N-terminal cysteine containing lipopeptide (GZ3.163) onto the polyethylene glycol polymer matrix and initiating gelation using thiol-ene click chemistry. The gels were prepared both in methanol and in water and were characterised using rheology, Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). Antibacterial and antibiofilm analyses revealed that the gels prepared in methanol have better antibacterial and antibiofilm activity. Additionally, a minimum peptide content of 0.5 wt% (relative to polymer content) is required to successfully inhibit the planktonic bacterial growth and disperse mature biofilms of P. aeruginosa and S. aureus. The antibacterial activity of these lipopeptide gels is mediated by a contact kill mechanism of action. The gels are non-haemolytic against mouse red blood cells and are non-cytotoxic against human dermal fibroblasts. Findings from this study show that battacin lipopeptide gels have the potential to be developed as novel topical antibacterial agents to combat skin infections, particularly caused by S. aureus.

Physical separation between the mammalian immune system and commensal bacteria is necessary to limit chronic inflammation. However, selective species of commensal bacteria can reside within intestinal-associated lymphoid tissues of healthy mammals. Here, we demonstrate that lymphoid tissue-resident commensal bacteria (LRC) colonized murine dendritic cells and modulate their cytokine production. In germ-free and antibiotic-treated mice, LRCs colonized intestinal-associated lymphoid tissues and induced multiple members of the IL-10 cytokine family, including dendritic cell-derived IL-10 and group 3 innate lymphoid cell (ILC3)-derived IL-22. Notably, IL-10 limited the development of pro-inflammatory Th17 cell responses, and IL-22 production enhanced LRC colonization in the steady state. Furthermore, LRC colonization protected mice from lethal intestinal damage in an IL-10-IL-10R-dependent manner. Collectively, our data reveal a unique host-commensal bacteria dialogue whereby selective subsets of commensal bacteria interact with dendritic cells to facilitate tissue-specific responses that are mutually beneficial for both the host and the microbe.

Holes were percussion drilled in Inconel 718 plates by a high intensity pulsed ultraviolet laser (266 and 355 nm) with 8 ns pulse width. It showed that shortening the laser wavelength resulted in thinner recast layers, less microcracks, and faster machining speed. In order to get high quality and fast speed in laser hole drilling, a two-step processing method was proposed and tested.

Micro-Raman spectroscopy was employed to investigate the structural changes of diamond films prepared by hot filament chemical vapor deposition and treated by femtosecond (fs) laser and nanosecond (ns) lasers. Breit–Wigner–Fano and Lorentzian line shape simulations were used to fit the spectra. For 266 nm ns laser treated samples, increasing laser power density results in the transformation of amorphous carbons in diamond films into nanocarbon clusters whose size increases and saturates rapidly at around 5.1 nm. At the same time, the Raman G peak position considerably shifts upwardly with increasing laser power density. The different change behavior of the nanocarbons and G peak is interpreted in light of the charge transfer from the graphite π bands to the localized edge states. As the 266 nm laser power density is high enough, a Raman peak in the range of 1150–1200 cm−1 appears, which is attributed to the presence of amorphous diamond. In the case of fs laser treated samples, much more power density (>1...

Type 2 inflammation underlies allergic diseases such as atopic dermatitis, which is characterized by the accumulation of basophils and group 2 innate lymphoid cells (ILC2s) in inflamed skin lesions. Although murine studies have demonstrated that cutaneous basophil and ILC2 responses are dependent on thymic stromal lymphopoietin, whether these cell populations interact to regulate the development of cutaneous type 2 inflammation is poorly defined. In this study, we identify that basophils and ILC2s significantly accumulate in inflamed human and murine skin and form clusters not observed in control skin. We demonstrate that murine basophil responses precede ILC2 responses and that basophils are the dominant IL-4–enhanced GFP-expressing cell type in inflamed skin. Furthermore, basophils and IL-4 were necessary for the optimal accumulation of ILC2s and induction of atopic dermatitis–like disease. We show that ILC2s express IL-4Rα and proliferate in an IL-4–dependent manner. Additionally, basophil-derived IL-4 was required for cutaneous ILC2 responses in vivo and directly regulated ILC2 proliferation ex vivo. Collectively, these data reveal a previously unrecognized role for basophil-derived IL-4 in promoting ILC2 responses during cutaneous inflammation.

Faulting is an important performance indicator for jointed concrete pavements since it is highly associated with pavement ride quality. Currently many state DOTs have considered faulting measurements as a component of network-level pavement survey and used various instruments to collect faulting data such as fault meter, inertial high speed profiler, and newly developed laser based 3D technologies. The manual faulting measurement approach is time consuming, labor intensive, and presents a potential safety hazard to operators and traveling public. For the inertial high speed profiler, the joint faulting measured at different lateral locations may be different as a result of the irregularities of the joint characteristics. Moreover, past studies indicated existing algorithms for automated joint detection and identification need to be further developed. In this study a masking filter and the template match based algorithm are employed to locate the potential slab joints, and subsequently faulting at each joint is measured in accordance with the revised AASHTO R36-04 protocol. As a result, the slab joint quantity and locations identified using the proposed method is compared with that identified using the downward spike algorithm applied in ProVAL. Comparisons of the data indicate the template matched algorithm produces better identification results than the downward spike algorithm. The faulting validation would be made in the future research based on actual faulting measurements.

In this paper, a new quantum state restoration scheme is proposed based on the environment-assisted error correction (EAEC) scheme. By introducing a weak measurement reversal (WMR) operation, we shall show how to recover an initial state of a quantum open system without invoking random unitary decompositions which are known to be absent in many important physical systems. We illustrate our new scheme and compare it with a scheme purely based on the WMR operation in the case of dissipative channel. In the proposed new scheme, the successful probability of recovering an unknown initial state can be significantly improved when the information obtained from an environment measurement is taken into account. Moreover, we show that the applicable range of our proposed scheme is wider than the EAEC scheme. Finally, the optimization of the successful probability for possible Kraus decompositions is discussed., 6 pages, 3 figures

The multidrug transporter breast cancer resistance protein (ABCG2) is upregulated in the mammary gland during lactation. We have shown that prolactin induces ABCG2 in human breast cancer cells via ...

Undaria pinnatifida is a species of brown seaweed known to contain rich amounts of fucoidan, a sulphated polysaccharide known to possess various biological activities. We isolated crude fucoidan (F0) from the sporophylls of U. pinnatifida grown in the Marlborough Sounds, New Zealand. Sulphate content, uronic acid content and molecular weight of F0 were 15.02%, 1.24% and >150 kDa, respectively. F0 was fractionated to yield three further fractions: F1, F2 and F3. Cytotoxicity of two major fractions was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The algal fucoidans specifically suppressed the proliferation of three cancer cell lines with less cytotoxicity against the normal cells. Selective cytotoxicity could relate to the distinctive structures of each fucoidan fraction. Results from this study provide evidence that fucoidan, especially from U. pinnatifida grown in New Zealand, possesses great potential to be used as a functional food to reduce cancer risk or supplement cancer treatment.

This study tested extracts from New Zealand seaweed Undaria pinnatifida containing fucoxanthin, in parallel with pure fucoxanthin, in nine human cancer cell lines, for anticancer activity. Growth inhibition effects of extracts from Undaria pinnatifida were found in all types of cancer cell lines in dose- and time- dependent manners. Cytotoxicity of fucoxanthin in three human non-cancer cell lines was also tested. Compared with pure fucoxanthin, our extracts containing low level of fucoxanthin were found to be more effective in inhibiting the growth of lung carcinoma, colon adenocarcinoma and neuroblastoma. Our results suggest that fucoxanthin is a functional biomaterial that may be used as a chemopreventive phytochemical or in combination chemotherapy. Furthermore, we show for the first time that some unknown compounds with potential selective anti-cancer effects may exist in extracts of New Zealand Undaria pinnatifida, and New Zealand Undaria pinnatifida could be used as a source for either functional biomaterial extraction or production of functional food.

We report the laser-induced periodic surface structure (LIPSS) with periodicity about a quarter of the laser wavelength on unpolished diamond film treated by a P-polarized femtosecond laser. The short period LIPSS is parallel to the laser polarization and independent on the incidence angle. The LIPSS perpendicular to the laser polarization with periodicity shorter than a third of the laser wavelength slightly dependent on the incidence angle is also observed as well as the LIPSS perpendicular to the laser polarization with periodicity dependent on the incidence angle. The results are explained by interference of the incident laser and surface scattered wave related to the excited electrons during laser interactions with diamond, being in excellent agreement with a previously developed theory.

We report on the topography of holes ablated by an ultrahigh intensity 355 and 266 nm laser with 8 ns pulse width in Ni-base superalloy Inconel 718. The origin of droplets, micropores, and microcracks on the surface of hole is identified. Qualitative differences in the characteristics of microcracks indicate that the dominant continuous microcracks result from thermal effects in 355 nm laser ablation, and the dominant island-chain microcrack result from photochemical effects in 266 nm laser ablation. In ultrahigh intensity laser ablation (>200 GW/cm2), the mechanical load on the surface is very significant to the resulting topography, and the grain boundary plays an important role in the origin of the micropores.