Cell-type-specific tumour sensitivity identified with a bromodomain targeting PROTAC in adenoid cystic carcinoma.

Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy with limited treatment options. The development of novel therapies is hindered by a lack of preclinical models. We have generated ACC patient-derived xenograft (PDX) lines that retain the physical and genetic properties of the original tumours, including the presence of the common MYB::NFIB or MYBL1::NFIB translocations. We have developed the conditions for the generation of both 2D and 3D tumour organoid patient-derived ACC models that retain MYB expression and can be used for drug studies. Using these models, we show in vitro and in vivo sensitivity of ACC cells to the bromodomain degrader, dBET6. Molecular studies show a decrease in BRD4 and MYB protein levels and target gene expression with treatment. The most prominent effect of dBET6 on tumours in vivo was a change in the relative composition of ACC cell types expressing either myoepithelial or ductal markers. We show that dBET6 inhibits the progenitor function of ACC cells, particularly in the myoepithelial marker-expressing population, revealing a cell-type-specific sensitivity. These studies uncover a novel mechanistic effect of bromodomain inhibitors on tumours and highlight the need to impact both cell-type populations for more effective treatments in ACC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Stable Q-switched and femtosecond mode-locked erbium-doped fiber laser based on a CuSe nanosheets saturable absorber.

Stable Q-switched and femtosecond mode-locked erbium-doped fiber laser (EDFL) have been achieved using CuSe nanosheets as novel saturable absorber (SA), where the CuSe nanosheets were prepared by a hydrothermal method. The nonlinear optical properties of CuSe nanosheets were measured using an Z-scan setup, revealing nonlinear absorption coefficients of -3.67 ± 0.22 cm GW-1 at 1560 nm. The prepared CuSe nanosheets were mixed with polyvinyl alcohol (PVA) to obtain a CuSe-PVA SA with a modulation depth of 3.8 ± 0.13%, and it was utilized to realize a Q-switched EDFL, obtaining the narrowest pulse duration of 1.29 µs and the maximum output power of 5.96 mW, which corresponds to a pulse energy of up to 103.7 nJ. In addition, CuSe nanosheets were deposited on a D-shaped fiber (DSF) to fabricate a CuSe-DSF SA with a modulation depth of 5.6 ± 0.17%, and it was utilized to realize a mode-locked EDFL. The mode-locked EDFL demonstrated a low threshold of only 42 mW, a pulse duration of 740 fs, and a maximum output power of 9.7 mW. Meanwhile, it exhibited a high signal-to-noise ratio of 72 dB. To the best of our knowledge, this is the first time of CuSe nanosheets as SA in EDFL. The results demonstrate that CuSe nanosheets are a highly promising nonlinear optical material with great potential for applications in ultrafast photonics.

Continuous-wave operation of a tandem optical parametric oscillator up to 5.19†µm based on periodically poled LiNbO3.

A continuous-wave, tandem optical parametric oscillator (TOPO) based on a MgO-doped periodically poled LiNbO3 (MgO:PPLN) is demonstrated. Because the MgO:PPLN is tandemly pumped by the OPO's signal beam, it outputs simultaneously two groups of signal and idler with a single pump source. The entire range spans from 1398 to 1490 nm, 1914 to 2107 nm, 3720 to 4444 nm, and 4849 to 5190 nm, which is limited by periods of the MgO:PPLN and cavity mirror coatings. The TOPO, whose oscillation threshold of pump power exceeds 7 W, can be easily triggered by marginally increasing the pump power as long as the OPO process occurs. The maximum idler powers are respectively 2.6 W (at 3896 nm) and 34 mW (at 4863 nm), and the corresponding signal powers are both nearly 100 mW.

Organizing Pneumonia in A Patient Double-Positive for ANCA and Anti-GBM Antibodies: A Case Report.

Both anti-glomerular basement membrane (GBM) disease and the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are common causes of pulmonary-renal syndrome. Organizing pneumonia (OP), a special pattern of interstitial lung disease, is extremely rare either in AAV or anti-GBM disease. We report an old woman presented with OP on a background of co-presentation with both ANCA and anti-GBM antibodies.

FSH may mediate the association between HbA1c and bone turnover markers in postmenopausal women with type 2 diabetes.

INTRODUCTION: Recent studies in postmenopausal women have found associations of follicle-stimulating hormone (FSH) levels with both glucose metabolism and bone turnover. The objective of the study was to investigate whether FSH may contribute to suppressed bone turnover markers (BTMs) in postmenopausal women with type 2 diabetes (T2D). MATERIALS AND METHODS: 888 postmenopausal women with T2D, 352 nondiabetes (prediabetes plus normoglycemia) were included from the METAL study. HbA1c, sex hormones, 25-hydroxy vitamin D (25(OH)D), serum procollagen type I N-terminal propeptide (P1NP), and ß-C-terminal telopeptide (ß-CTX) were measured. RESULTS: P1NP and ß-CTX decreased in postmenopausal T2D women compared with nondiabetes controls (both p < 0.001). The major factors responsible for the changes in P1NP were HbA1c (ß = - 0.050, p < 0.001), 25(OH)D (ß = - 0.003, p = 0.006), FSH (ß = 0.001, p = 0.044) and metformin (ß = - 0.109, p < 0.001), for ß-CTX were HbA1c (ß = - 0.049, p < 0.001), body mass index (BMI) (ß = - 0.011, p = 0.005), 25(OH)D (ß = - 0.003, p = 0.003), FSH (ß = 0.002, p = 0.022) and metformin (ß = - 0.091, p = 0.001) in postmenopausal T2D women based on multivariate regression analysis. With the increase in HbA1c, FSH decreased significantly (p for trend < 0.001). Mediation analysis demonstrated that FSH partly mediated the suppression of LnP1NP and Lnß-CTX by HbA1c (ß = - 0.009 and - 0.010, respectively), and Lnß-CTX by BMI (ß = - 0.015) when multiple confounders were considered (all p < 0.05). CONCLUSION: HbA1c was the crucial determinant contributing to the suppression of BTMs. FSH might play a novel mediation role in BTM suppression due to HbA1c or BMI.

Renal Amyloidosis Secondary to ANCA-Associated Vasculitis: A Case Report.

Renal amyloidosis secondary to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is extremely rare. Here, we reported a 77-year-old woman with ANCA-associated vasculitis. Renal biopsy with Masson trichrome staining showed pauci-immune crescentic glomerulonephritis, and electron microscopy showed amyloid deposition in the mesangial area. Immunofluorescence revealed kappa light chain and lambda light chain negative. Bone marrow biopsy revealed no clonal plasma cell. Finally, she was diagnosed as ANCA-associated vasculitis with secondary renal amyloid A amyloidosis.

Rational design and fabrication of an alkali-induced O/W emulsion stabilized with cellulose nanofibrils (CNFs): implication for eco-friendly and economic oil recovery application.

In this work, an alkali-induced oil in water (O/W) emulsion stabilized with cellulose nanofibrils (CNFs) was proposed to advance the development of enhanced oil recovery (EOR) approaches. The reactive species in the crude oil were first determined by FT-ICR MS. Subsequently, direct measurements of emulsion rheology, morphology, drop size distribution, and interfacial tensions (IFTs) were performed. Particular interest was placed on the stability and variation of the average drop diameter of the emulsions to reveal the underlying stabilizing mechanisms. The results showed that the introduction of L-CNFs (containing lignin segment) and CNFs could significantly prohibit the coalescence of drops and thus improve the stability of the emulsions. L-CNFs and CNFs were irreversibly absorbed at the oil-water interface forming a solid "armor" on the drops with 63.1% of the oil-water interface being covered by CNFs. This finally led to the generation of highly stable O/W emulsions. This work demonstrated the potential of CNFs as promising "green" interface stabilizers for emulsion flooding EOR particularly for in situ surfactant generation scenarios.

Synthesis and biocompatibility of an argatroban-modified polysulfone membrane that directly inhibits thrombosis.

Anticoagulation therapy plays a vital role in the prevention of blood clot formation during hemodialysis and hemofiltration, especially for critical care patients. Here, we synthesized a novel argatroban (Arg)-modified polysulfone (PSf) membrane for anticoagulation. Arg was grafted onto the PSF membrane via chemical modification to increase membrane hydrophilicity. Protein adsorption, coagulation, as well as activation of platelets and complement systems were greatly reduced on the Arg-modified PSf membrane. Thus, the recalcification time and the activated partial thrombin time (APTT) were increased after the modification. In comparison with the pristine PSf membrane, the Arg-modified PSf membrane showed better hemocompatibility and anticoagulation properties, indicating its potential for applications in hemodialysis and hemofiltration. Modification of the PSf membrane has been investigated in attempts to further enhance the anticoagulation properties of the hemodialysis membranes, including a heparin-modified PSf membrane. However, heparin can inhibit plasma-free thrombin, and cause the occurrence of heparin-induced thrombocytopenia (HIT), which increases the risk of bleeding during dialysis in critical care patients. To address this problem, we modified PSf membrane with as a novel direct thrombin inhibitors, argatroban (Arg). It can reversibly bind to thrombin, inhibiting not only the plasma-free thrombin in the blood, but also clot-bound thrombin.

83.4 W, 17.69 kHz spectral bandwidth, continuous-wave, beam densely folded Innoslab amplifier.

Combined with the advantages of the narrow bandwidth of a non-planar ring oscillator seed laser and the structure of a direct pumped Innoslab amplifier, a high-efficiency and high-power continuous-wave (CW) single-frequency laser was obtained by densely folding the seed laser beam in an Innoslab amplifier with a wedged multi-folded configuration. A maximum output power of 83.4 W of a single-frequency amplifier with a bandwidth of 17.69 kHz was obtained under a pump power of 234 W, corresponding to an optical-to-optical conversion efficiency of 33.2%. The beam quality factor M2 at the maximum output power in horizontal and vertical directions was measured to be 1.15 and 1.24, respectively. The long-term power instability in 2 h was less than 1.63%.

Emodin alleviates intestinal mucosal injury in rats with severe acute pancreatitis via the caspase-1 inhibition.

BACKGROUND: Emodin, a traditional Chinese medicine, has a therapeutic effect on severe acute pancreatitis (SAP), whereas the underlying mechanism is still unclear. Studies showed that the intestinal mucosa impairment, and subsequent release of endotoxin and proinflammatory cytokines such as IL-1ß, which further leads to the dysfunction of multiple organs, is the potentially lethal mechanism of SAP. Caspase-1, an IL-1ß-converting enzyme, plays an important role in this cytokine cascade process. Investigation of the effect of emodin on regulating the caspase-1 expression and the release proinflammatory cytokines will help to reveal mechanism of emodin in treating SAP. METHODS: Eighty Sprague-Dawley rats were randomly divided into four groups (n=20 each group): SAP, sham-operated (SO), emodin-treated (EM) and caspase-1 inhibitor-treated (ICE-I) groups. SAP was induced by retrograde infusion of 3.5% sodium taurocholate into the pancreatic duct. Emodin and caspase-1 inhibitor were given 30 minutes before and 12 hours after SAP induction. Serum levels of IL-1ß, IL-18 and endotoxin, histopathological alteration of pancreas tissues, intestinal mucosa, and the intestinal caspase-1 mRNA and protein expressions were assessed 24 hours after SAP induction. RESULTS: Rats in the SAP group had higher serum levels of IL-1ß and IL-18 (P<0.05), pancreatic and gut pathological scores (P<0.05), and caspase-1 mRNA and protein expressions (P<0.05) compared with the SO group. Compared with the SAP group, rats in the EM and ICE-I groups had lower IL-1ß and IL-18 levels (P<0.05), lower pancreatic and gut pathological scores (P<0.05), and decreased expression of intestine caspase-1 mRNA (P<0.05). Ultrastructural analysis by transmission electron microscopy found that rats in the SAP group had vaguer epithelial junctions, more disappeared intercellular joints, and more damaged intracellular organelles compared with those in the SO group or the EM and ICE-I groups. CONCLUSIONS: Emodin alleviated pancreatic and intestinal mucosa injury in experimental SAP. Its mechanism may partly be mediated by the inhibition of caspase-1 and its downstream inflammatory cytokines, including IL-1ß and IL-18. Our animal data may be applicable in clinical practice.

Multi-layered black phosphorus as saturable absorber for pulsed Cr:ZnSe laser at 2.4 µm.

A high-quality black phosphorus (BP) saturable-absorber mirror (SAM) was successfully fabricated with the multi-layered BP, prepared by liquid-phase exfoliation (LPE) method. The modulation depth and saturation power intensity of BP absorber were measured to be 10.7% and 0.96 MW/cm(2), respectively. Using the BP-SAM, we experimentally demonstrated the mid-infrared (mid-IR) pulse generation from a BP Q-switched Cr:ZnSe laser for the first time to our best knowledge. Stable Q-switched pulse as short as 189 ns with an average output power of 36 mW was realized at 2.4 µm, corresponding to a repetition rate of 176 kHz and a single pulse energy of 205 nJ. Our work sufficiently validated that multi-layer BP could be used as an optical modulator for mid-IR pulse laser sources.

Low vitamin D levels and non-alcoholic fatty liver disease, evidence for their independent association in men in East China: a cross-sectional study (Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China)).

Recent studies have suggested an association between vitamin D and non-alcoholic fatty liver disease (NAFLD); however, some results are subject to debate. This study was carried out to evaluate the correlation between NAFLD and vitamin D in men and women in East China. The data were obtained from a cross-sectional study that focused on the health and metabolic status of adults in sixteen areas of East China. According to ultrasonic assessments, the patients were divided into normal and NAFLD groups. Demographic characteristics and biochemical measurements were obtained. Binary logistic regression analysis was used to explore the association. In total, 5066 subjects were enrolled, and 2193 (43·3 %) were diagnosed with NAFLD; 84·56 % of the subjects showed vitamin D deficiency. Subjects with high vitamin D levels had a lower prevalence of NAFLD, particularly male subjects. Within the highest quartile of vitamin D levels, the prevalence of NAFLD was 40·8 %, whereas the lowest quartile of vitamin D levels showed a prevalence of 62·2 %, which was unchanged in women across the vitamin D levels. Binary logistic analysis showed that decreased vitamin D levels were associated with an increased risk of NAFLD (OR 1·54; 95 % CI 1·26, 1·88). This study suggests that vitamin D levels are significantly associated with NAFLD and that vitamin D acts as an independent factor for NAFLD prevalence, particularly in males in East China. Vitamin D interventional treatment might be a new target for controlling NAFLD; elucidating the mechanism requires further research.

High power single-frequency Innoslab amplifier.

A laser diode array (LDA) end-pumped continuous-wave single-frequency Innoslab amplifier has been demonstrated. The Gaussian ray bundle method was used to model the light propagation in the Innoslab amplifier for the first time to the best of our knowledge. With discrete reflectors, the maximum output of 60 W with a linewidth of 44 MHz was achieved under the pump power of 245 W, corresponding to the optical-optical efficiency of 24.5%. The beam quality factor M2 at the output power of 51 W in the horizontal and vertical direction was measured to be 1.4 and 1.3, respectively. The long-term power instability in 2 h was less than 0.25%.

759 fs pulse generation with Nd3+-doped CNGS ordered crystal based on a semiconductor saturable absorber mirror.

A diode-pumped passively continuous wave mode-locked laser at 1064.2 nm based on an ordered Nd:CNGS crystal has been experimentally investigated (for the first time, to our knowledge). Stable mode-locked pulses with a duration of 759 fs were produced at a repetition rate of 43.2 MHz. It is the shortest pulse generation of mode-locked lasers based on Nd3+-doped ordered crystal, as far as we know. A maximum average mode-locked output power of 133 mW was obtained at the absorbed pumped power of 6.7 W, and corresponding single-pulse energy and peak power were determined to be 3.1 nJ and 4.1 kW, respectively. The results indicate that the Nd:CNGS as an ordered crystal is indeed a potential candidate as a femtosecond laser gain medium.

Exfoliated layers of black phosphorus as saturable absorber for ultrafast solid-state laser.

High-quality black phosphorus (BP) saturable absorber mirror (SAM) was successfully fabricated with few-layered BP (phosphorene). By employing the prepared phosphorene SAM, we have demonstrated ultrafast pulse generation from a BP mode-locked bulk laser for the first time to our best knowledge. Pulses as short as 6.1 ps with an average power of 460 mW were obtained at the central wavelength of 1064.1 nm. Considering the direct and flexible band gap for different layers of phosphorene, this work may provide a possible method for fabricating BP SAM to achieve ultrafast solid-state lasers in IR and mid-IR wavelength region.

The function of resilin in honeybee wings.

The present work aimed to reveal morphological characteristics of worker honeybee (Apis mellifera) wings and demonstrate the function of resilin on camber changes during flapping flight. Detailed morphological investigation of the wings showed that different surface characteristics appear on the dorsal and ventral side of the honeybee wings and the linking structure connecting the forewing and hindwing plays an indispensable role in honeybee flapping flight. Resilin stripes were found on both the dorsal and ventral side of the wings, and resilin patches mostly existed on the ventral side. On the basis of resilin distribution, five flexion lines and three cambered types around the lines of passive deformation of the coupled-wing profile were obtained, which defined the deformation mechanism of the wing along the chord, i.e. concave, flat plate and convex. From a movie obtained using high-speed photography from three orthogonal views of free flight in honeybees, periodic changes of the coupled-wing profile were acquired and further demonstrated that the deformation mechanism is a fundamental property for variable deformed shapes of the wing profile during flapping flight, and, in particular, the flat wing profile achieves a nice transition between downstrokes and upstrokes.

High-Flux Hemodialysis Benefits Hemodialysis Patients by Reducing Serum FGF-23 Levels and Reducing Vascular Calcification.

BACKGROUND: High- and low-flux hemodialysis (HFHD and LFHD, respectively) are dialysis procedures designed to eliminate blood toxins that accumulate in end-stage renal disease. HFHD may reduce vascular calcification by removing serum fibroblast growth factor 23 (FGF-23). However, whether HFHD is better than LFHD is still under debate. We therefore compared the efficacy of HFHD and LFHD in controlling FGF-23 and vascular calcification. MATERIAL AND METHODS: Fifty hemodialysis patients were recruited and randomly treated with either HFHD or LFHD. Fasting venous blood was collected at baseline, six months, and twelve months after the treatment. We then measured levels of FGF-23, calcium, phosphorus, parathyroid hormone, and alkaline phosphatase. Further, abdominal lateral radiographs were taken to calculate aorta abdominalis calcification scores (AACs). RESULTS: Compared to the LFHD group, FGF-23 and AACs in the HFHD group significantly decreased after 12 months treatment (p=0.049 and p=0.002, respectively). AACs were positively correlated with FGF-23 in all patients (p=0.004), the HFHD group alone (p=0.040), and the LFHD group alone (p=0.037). We also found that older patients, patients with higher blood phosphorus levels, and higher FGF-23 levels had an increased risk of aorta abdominalis calcification (p=0.048, p=0.003, p=0.001, respectively). HFHD was more able to reduce the risk of aorta abdominalis calcification than LFHD (p=0.003). CONCLUSIONS: FGF-23 is an independent risk factor for the development of vascular calcification. HFHD may benefit hemodialysis patients by reducing serum FGF-23 levels and controlling vascular calcification.

Passively Q-switched mode-locking of Tm:YAP laser based on Cr:ZnS saturable absorber.

Using a Cr:ZnS wafer as the saturable absorber, diode-pumped passively Q-switched mode-locking of a Tm:YAP laser at 1976 nm has been realized for the first time, to the best of our knowledge, and nearly 100% modulation depth of Q-switched mode-locking was achieved. The width of the mode-locked pulse was estimated to be about 980 ps with a repetition rate of 350 MHz within a roughly 300-ns-long Q-switched pulse envelope. A maximum output power of 940 mW was obtained, corresponding to the Q-switched pulse energy of 0.55 mJ. The emission wavelength evolution between the continuous-wave and Q-switched mode-locked operations was presented and discussed. The experimental results indicate that the Cr:ZnS absorber is a promising saturable absorber for passively Q-switched mode-locking operation around 2 µm.

Passively Q-switched 2 µm Tm:YAP laser based on graphene saturable absorber mirror.

Using high-quality single-layer graphene as a saturable absorber, Tm:YAlO3 (Tm:YAP) crystal as the gain medium, we demonstrated a laser-diode-pumped, compact, passively Q-switched (PQS) solid-state laser in the 2 µm region. The maximum average output power was 362 mW, with the corresponding largest pulse repetition rate and pulse energy of 42.4 kHz and 8.5 µJ, respectively. Under the same pump power, the pulse width of 735 ns was obtained, which is, to our best knowledge, the shortest pulse width among Tm-doped solid-state PQS lasers using graphene saturable absorber mirrors.

Antitumor activity of recombinant antimicrobial peptide penaeidin-2 against kidney cancer cells.

Penaeidin-2 (Pen-2) is an important antimicrobial peptide derived from the Pacific white shrimp, Penaeus vannamei, and possesses both antibacterial and antifungal activities. Recent studies suggest that recombinant penaeidins show similar activities to the native Pen-2 protein. Previous researches have shown that some antimicrobial peptides (AMPs) exhibit cytotoxic activity against cancer cells. To date, there have been no studies on the antitumor effects of Pen-2. This study evaluated the potential of recombinant pen-2 (rPen-2) in the selective killing of kidney cancer cell lines ACHN and A498, and its action mechanism. MTT assays found the maximal growth inhibition of HK-2, ACHN and A498 cells treated with 100 µg/mL rPen-2 at 48 h was 13.2%, 62.4%, and 70.4%, respectively. DNA-specific fluorescent dye staining showed a high percentage of apoptosis on cancer cells. Flow cytometry revealed that the apoptosis rate of HK-2, ACHN and A498 cells was 15.2%, 55.2%, and 61.5% at 48 h respectively, suggesting that rPen-2 induced higher apoptosis rate in cancer cells than in HK-2 cells. Laser confocal scanning microscopy demonstrated that the plasma membrane was the key site where rPen-2 interacted with and destroyed tumor cells. Scanning electron microscopy showed the morphologic changes of the cell membranes of kidney cancer cells treated with rPen-2. These results suggest that rPen-2 is a novel potential therapeutic agent that may be useful in treating kidney cancers.