Mining the interpretable prognostic features from pathological image of intrahepatic cholangiocarcinoma using multi-modal deep learning.

BACKGROUND: The advances in deep learning-based pathological image analysis have invoked tremendous insights into cancer prognostication. Still, lack of interpretability remains a significant barrier to clinical application. METHODS: We established an integrative prognostic neural network for intrahepatic cholangiocarcinoma (iCCA), towards a comprehensive evaluation of both architectural and fine-grained information from whole-slide images. Then, leveraging on multi-modal data, we conducted extensive interrogative approaches to the models, to extract and visualize the morphological features that most correlated with clinical outcome and underlying molecular alterations. RESULTS: The models were developed and optimized on 373 iCCA patients from our center and demonstrated consistent accuracy and robustness on both internal (n = 213) and external (n = 168) cohorts. The occlusion sensitivity map revealed that the distribution of tertiary lymphoid structures, the geometric traits of the invasive margin, the relative composition of tumor parenchyma and stroma, the extent of necrosis, the presence of the disseminated foci, and the tumor-adjacent micro-vessels were the determining architectural features that impacted on prognosis. Quantifiable morphological vector extracted by CellProfiler demonstrated that tumor nuclei from high-risk patients exhibited significant larger size, more distorted shape, with less prominent nuclear envelope and textural contrast. The multi-omics data (n = 187) further revealed key molecular alterations left morphological imprints that could be attended by the network, including glycolysis, hypoxia, apical junction, mTORC1 signaling, and immune infiltration. CONCLUSIONS: We proposed an interpretable deep-learning framework to gain insights into the biological behavior of iCCA. Most of the significant morphological prognosticators perceived by the network are comprehensible to human minds.

[Implementation Status of Palliative Care for Patients Died in Peking Union Medical College Hospital,2019].

Objective To reveal the current situation of palliative care for patients who died in Peking Union Medical College Hospital,so as to guide the practice of palliative care for patients in terminal stage. Methods A retrospective study was conducted on patients who died in Peking Union Medical College Hospital from January 1,2019 to December 31,2019.The general clinical data of the patients,whether they received palliative care,and the treatment details including invasive rescue measures,symptom controlling,and psychological,social,and spiritual care status before dying were collected for descriptive analysis. Results A total of 244 inpatients died in 2019,including 135 males and 109 females,with an average age of (65.9±16.4) years (1 day to 105 years).Among the 244 patients,112 (45.9%) died of neoplastic diseases and 132 (54.1%) died of non-neoplastic diseases.Sixty-one (25.0%) patients received palliative care before death,and they were mainly distributed in internal medicine departments such as nephrology (100.0%),gastroenterology (80.0%),and geriatrics (72.7%).Twenty-nine patients received sound palliative care,with all symptoms under control and no invasive treatment before death,and twenty-six patients received psychological,social,and spiritual care.Compared with the patients who were not exposed to the concept of palliative care,the patients who received palliative care showed decreased probabilities of cardiopulmonary resuscitation (0 vs 20.2%;χ2=13.009,P<0.001),tracheal intubation (3.3% vs 48.6%;χ2=38.327,P<0.001),and invasive mechanical ventilation (4.9% vs 47.5%;χ2=33.895,P<0.001) and an increased probability of psychological,social,and spiritual care (54.1% vs 2.4%;χ2=91.486,P<0.001). Conclusion The concept of palliative care has a positive impact on the death of end-stage patients.Palliative care services can increase the probability of end-stage patients receiving psychological,social,and spiritual care and reduce the use of invasive treatment.

[Effect of Concept and Practice of Palliative Care on the Death Status of Patients in Peking Union Medical College Hospital].

Objective To analyze the changes of death status of the inpatients in Peking Union Medical College Hospital before and after the development of palliative care.Methods All the death cases of Peking Union Medical College Hospital in 2013 (384 cases) and 2019 (244 cases) were included in this study,and the general information of the patients and the details of diagnosis and treatment before death were collected.Results The departments of intensive care,emergency,and respiratory diseases and the international medical services had highest number of deaths in both 2013 and 2019,with the cumulative constituent ratios of 67.7% and 62.7%,respectively.The number of clinical departments that involved or implemented palliative care increased from 7 in 2013 to 14 in 2019.The number of patients who died in 2019 and exposed to palliative care increased (P<0.001) compared with that in 2013,and increasing patients received humanistic care (P<0.001).Compared with 2013,2019 witnessed reducing patients receiving vasoactive drugs (P=0.006),cardiopulmonary resuscitation (P=0.002),endotracheal intubation (P=0.002),invasive mechanical ventilation (P<0.001),and invasive operation (P<0.001) before death in 2019.Conclusion The concept and practice of palliative care have significantly reduced the proportion of terminal patients receiving traumatic treatment.

A Photosensitizing Metal-Organic Framework as a Tandem Reaction Catalyst for Primary Alcohols from Terminal Alkenes and Alkynes.

Owing to the wide and growing demand for primary alcohols, the development of efficient catalysts with high regioselectivity remains a worthwhile pursuit. However, according to Markovnikov's rule, it is a challenge to obtain primary alcohols with high yields and regioselectivity from terminal alkenes or alkynes. Herein, we report the synthesis of a photosensitizing two-dimensional (2D) metal-organic framework (MOF) from cyclic trinuclear copper(I) units (Cu-CTUs) and a boron dipyrro-methene (Bodipy) ligand. The MOF features broadband light absorption, excellent photoinduced charge separation efficiency, and photochemical properties. By integrating the copper-catalyzed hydroboration and photocatalyzed aerobic oxidation, it can catalyze terminal alkenes and alkynes to produce primary alcohols via a one-pot tandem reaction with excellent regioselectivity, good overall yields in two-step reactions (up to 85 %), broad substrate compatibility (32 examples) and good reusability under mild conditions.

Ultrathin Metal-Organic Framework Nanosheets Exhibiting Exceptional Catalytic Activity.

Two-dimensional (2D) metal-organic framework nanosheets (MONs) or membranes are classes of periodic, crystalline polymeric materials that may show unprecedented physicochemical properties due to their modular structures, high surface areas, and high aspect ratios. Yet preparing 2D MONs from multiple components and two different types of polymerization reaction remains challenging and less explored. Here, we report the synthesis of MOF films via interfacial polymerization, which involves three active monomers for simultaneous polycondensation and polycoordination taking place in a confined interface. The well-defined lamellar structure of the MOF films allowed feasible and scalable exfoliation to produce free-standing 2D MONs with high aspect ratio up to 2000:1 and ultrathin thickness (∼1.7 nm). The pore structure was revealed by high-resolution TEM images with near-atomic precision. The imide-linkage of MONs provided superior thermal (up to 530 °C) and good chemical stability in the pH range from 3 to 12. More importantly, the MONs exhibited exceptional catalytic activity and superior reusability for the hydroboration reactions of alkynes, in which the turnover frequency (TOF) reached 41734 h-1, which is 2-4 orders of magnitude greater than that reported for homogeneous and heterogeneous catalysts.

Optical Control of Multistage Phase Transition via Phonon Coupling in MoTe_{2}.

The temporal characters of laser-driven phase transition from 2H to 1T^{'} has been investigated in the prototype MoTe_{2} monolayer. This process is found to be induced by fundamental electron-phonon interactions, with an unexpected phonon excitation and coupling pathway closely related to the nonequilibrium relaxation of photoexcited electrons. The order-to-order phase transformation is dissected into three substages, involving energy and momentum scattering processes from optical (A_{1}^{'} and E^{'}) to acoustic phonon modes [LA(M)] in subpicosecond timescale. An intermediate metallic state along the nonadiabatic transition pathway is also identified. These results have profound implications on nonequilibrium phase engineering strategies.

Synthesis of Bioactive Compounds from 3-Carene (II): Synthesis, Antifungal Activity and 3D-QSAR Study of (Z)- and (E)-3-Caren-5-One Oxime Sulfonates.

A series of novel (Z)- and (E)-3-caren-5-one oxime sulfonates were designed and synthesized in search of potent antifungal agents. The structures of the intermediates and target compounds were confirmed by UV-Vis, FTIR, NMR, and ESI-MS. The in vitro antifungal activity of the target compounds was preliminarily evaluated against Cercospora arachidicola, Physalospora piricola, Alternaria solani, Rhizoeotnia solani, Bipolaris maydis and Colleterichum orbicalare at 50 µg/mL. The bioassay results indicated that the target compounds exhibited the best antifungal activity against P. piricola, in which compounds 4b, 4f, 4m, 4e, 4j, 4l, 4y, 4d, and 4p had excellent inhibition rates of 100%, 100%, 100%, 92.9%, 92.9%, 92.9%, 92.9%, 85.7%, and 85.7%, respectively, showing much better antifungal activity than that of the commercial fungicide chlorothanil. Both the compounds 4y and 4x displayed outstanding antifungal activity of 100% against B. myadis, and the former also displayed outstanding antifungal activity of 100% against R. solani. In order to design more effective antifungal compounds against P. piricola, the analysis of three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out using the CoMFA method, and a reasonable and effective 3D-QSAR model (r² = 0.990, q² = 0.569) has been established.

Diastereodivergent α-Homoallylation of Cyclic Enones.

α,ß-Unsaturated carbonyls are essential structural motifs for nucleophiles of disease-related proteins. Methods for stereoselective functionalizations at the α-position include the Morita-Baylis-Hillman, Negishi, Sonogashira, Stille, and Rauhut-Currier reactions. Described here is a method for the diastereodivergent α-homoallylation of cyclic enones via a sequence of conjugate addition, aldol condensation, and diastereoselective [3,3]-sigmatropic rearrangement. Mechanistic investigations revealed that the [3,3]-sigmatropic rearrangement proceeds with transfer of chirality. These inspire a photocatalyzed olefin isomerization of the aldol condensation product leading to a highly diastereoselective [3,3]-sigmatropic rearrangement to furnish the α-homoallylation of cyclic enones. Importantly, this photocatalyzed olefin isomerization/diastereoselective [3,3]-sigmatropic rearrangement reaction sequence permits a full stereocontrol of the exo-ß-position featuring an allyl group as a synthetic functional handle.

Reversible modulation of interlayer stacking in 2D copper-organic frameworks for tailoring porosity and photocatalytic activity.

The properties of two-dimensional covalent organic frameworks (2D COFs), including porosity, catalytic activity as well as electronic and optical properties, are greatly affected by their interlayer stacking structures. However, the precise control of their interlayer stacking mode, especially in a reversible fashion, is a long-standing and challenging pursuit. Herein, we prepare three 2D copper-organic frameworks, namely JNM-n (n = 7, 8, and 9). Interestingly, the reversible interlayer sliding between eclipsed AA stacking (i.e., JNM-7-AA and JNM-8-AA) and staggered ABC stacking (i.e., JNM-7-ABC and JNM-8-ABC) can be achieved through environmental stimulation, which endows reversible encapsulation and release of lipase. Importantly, JNM-7-AA and JNM-8-AA exhibit a broader light absorption range, higher charge-separation efficiency, and higher photocatalytic activity for sensitizing O2 to 1O2 and O2•- than their ABC stacking isostructures. Consequently, JNM-8-AA deliver significantly enhanced photocatalytic activities for oxidative cross-coupling reactions compared to JNM-8-ABC and other reported homogeneous and heterogeneous catalysts.

Single-shot ultrafast terahertz photography.

Multidimensional imaging of transient events has proven pivotal in unveiling many fundamental mechanisms in physics, chemistry, and biology. In particular, real-time imaging modalities with ultrahigh temporal resolutions are required for capturing ultrashort events on picosecond timescales. Despite recent approaches witnessing a dramatic boost in high-speed photography, current single-shot ultrafast imaging schemes operate only at conventional optical wavelengths, being suitable solely within an optically-transparent framework. Here, leveraging on the unique penetration capability of terahertz radiation, we demonstrate a single-shot ultrafast terahertz photography system that can capture multiple frames of a complex ultrafast scene in non-transparent media with sub-picosecond temporal resolution. By multiplexing an optical probe beam in both the time and spatial-frequency domains, we encode the terahertz-captured three-dimensional dynamics into distinct spatial-frequency regions of a superimposed optical image, which is then computationally decoded and reconstructed. Our approach opens up the investigation of non-repeatable or destructive events that occur in optically-opaque scenarios.

NIR C-Myc Pu22 G-quadruplex probe as a photosensitizer for bioimaging and antitumor study.

Despite the fact that C-Myc G-quadruplex in the oncogene promoter regions is one of the crucial targets of antitumor drugs, the selectivities and proliferation inhibitions of its probes towards tumor cells remain a big challenge. Until now, no effective C-Myc G-quadruplex probes have been reported as a photosensitizer to increase their antitumor activities. Here, the first NIR C-Myc G-quadruplex probe PDS-SQ has been designed, comprising a G-quadruplex binder PDS and a squaraine dye SQ as a photosensitizer. Conjugate PDS-SQ could selectively NIR image C-Myc Pu22 G-quadruplex in tumor cells, and show stronger antitumor activity in the irradiation by a chemo-photodynamic method than in the dark. The study provides a new way to develop the novel NIR C-Myc G-quadruplex probes with more potent antitumor activities.

Water-solubility croconic acid-bisindole dye with morpholine ring for tumor NIRF/PA imaging and photothermal therapy activated by lysosome pH-response.

A novel croconic acid-bisindole dye CR-630 with a morpholine ring showed good water-solubility and obvious lysosome-targeting. The protonation of the nitrogen atom in the indole and lysosome-targeting of morpholine ring let it exhibit stronger pH-responsive NIR/PA imaging and photothermal effect in the lysosome acidic microenvironment (pH 4.0-5.5) than in the tumor acidic microenvironment. In the animal study, compound CR-630 could NIRF/PA image in the tumor tissues in 1.5-2.0 h, effectively inhibit the growth of the tumor, and even ablate the tumor at the drug dose of 1 mg/kg. It also demonstrated good biosafety. This study gives a new idea to develop water-solubility organic dyes with lysosome targeting, stronger pH-responsive NIRF/PA imaging and PTT for breast cancer.

Single aromatics sulfonamide substituted dibenzothiazole squaraines for tumor NIR imaging and efficient photodynamic therapy at low drug dose.

On the base of the zwiterionic dibenzothiazole squaraine SQ, five cationic aromatics sulfonamide substituted dibenzothiazole squaraines SQ-D1 âˆ¼ 5 have been designed and synthesized. Through the formation of the cationic compound, a higher rigid structure and the addition of the strong electron-withdrawing group (-CN), an ideal photosensitizer SQ-D2 has been gotten. In all the sulfonaminosquaraines, compound SQ-D2 exhibited the highest ROS generation efficacy and photostability. It also showed the highest photo-cytotoxicity (IC50 = 0.25 ± 0.08 µM), very low dark-cytotoxicity and the excellent cell uptake. In animal study, it not only showed the effective tumor retention and the easy removal from the body, but also exhibited the effective PDT efficacy at low drug dose (0.15 mg/kg) and the good biocompatibility. Furthermore, photosensitizer SQ-D2 as a single component exhibited greater potential than clinically approved photosensitizer m-THPC and some nanomaterials with photosensitizers in PDT therapy towards human breast cancer. This work provides a new perspective to develop the ideal photosensitizer of the squaraine dyes.

Versatile metal-wire waveguides for broadband terahertz signal processing and multiplexing.

Waveguides play a pivotal role in the full deployment of terahertz communication systems. Besides signal transporting, innovative terahertz waveguides are required to provide versatile signal-processing functionalities. Despite fundamental components, such as Bragg gratings, have been recently realized, they typically rely on complex hybridization, in turn making it extremely challenging to go beyond the most elementary functions. Here, we propose a universal approach, in which multiscale-structured Bragg gratings can be directly etched on metal-wires. Such an approach, in combination with diverse waveguide designs, allows for the realization of a unique platform with remarkable structural simplicity, yet featuring unprecedented signal-processing capabilities. As an example, we introduce a four-wire waveguide geometry, amenable to support the low-loss and low-dispersion propagation of polarization-division multiplexed terahertz signals. Furthermore, by engraving on the wires judiciously designed Bragg gratings based on multiscale structures, it is possible to independently manipulate two polarization-division multiplexed terahertz signals. This platform opens up new exciting perspectives for exploiting the polarization degree of freedom and ultimately boosting the capacity and spectral efficiency of future terahertz networks.

LncSNHG1 Promoted CRC Proliferation through the miR-181b-5p/SMAD2 Axis.

Objective: To investigate the effects of LncRNA SNHG1 on the proliferation, migration, and epithelial-mesenchymal transition (EMT) of colorectal cancer cells (CRCs). Methods: 4 pairs of CRC tissue samples and their corresponding adjacent samples were analyzed by the human LncRNA microarray chip. The expression of LncSNHG1 in CRC cell lines was verified by qRT-PCR. Colony formation assays and CCK8 assays were applied to study the changes in cell proliferation. The transwell assay and wound healing experiments were used to verify the cell invasion and migration. EMT progression was confirmed finally. Results: LncSNHG1 was overexpressed both in CRC tissues and cell lines, while the miR-181b-5p expression was decreased in CRC cell lines. After knock-down of LncSNHG1, the proliferation, invasion, and migration of HT29 and SW620 cells were all decreased. Meanwhile, LncSNHG1 enhanced EMT progress through regulation of the miR-181b-5p/SMAD2 axis. Conclusion: LncSNHG1 promotes colorectal cancer cell proliferation and invasion through the miR-181b-5p/SMAD2 axis.

Manipulating Weyl quasiparticles by orbital-selective photoexcitation in WTe2.

Optical control of structural and electronic properties of Weyl semimetals allows development of switchable and dissipationless topological devices at the ultrafast scale. An unexpected orbital-selective photoexcitation in type-II Weyl material WTe2 is reported under linearly polarized light (LPL), inducing striking transitions among several topologically-distinct phases mediated by effective electron-phonon couplings. The symmetry features of atomic orbitals comprising the Weyl bands result in asymmetric electronic transitions near the Weyl points, and in turn a switchable interlayer shear motion with respect to linear light polarization, when a near-infrared laser pulse is applied. Consequently, not only annihilation of Weyl quasiparticle pairs, but also increasing separation of Weyl points can be achieved, complementing existing experimental observations. In this work, we provide a new perspective on manipulating the Weyl node singularity and coherent control of electron and lattice quantum dynamics simultaneously.

G-quadruplex binder pyridostatin as an effective multi-target ZIKV inhibitor.

At present, there are still no anti-Zika virus (ZIKV) drugs or vaccines approved by FDA with accurate targets and antiviral mechanisms. Considering the RNA G-quadruplex sequences in ZIKV genome, it is very meaningful to develop G-quadruplex binders as potential anti-ZIKV drugs with novel and accurate targets. In this paper, five classical G-quadruplex binders including Ber, Braco 19, NiL, 360A and PDS have been chosen to discuss their interaction with ZIKV RNA G-quadruplexes. PDS shows higher binding affinity and thermal stability than the other G-quadruplex binders. This property is further evidenced in cells by immunofluorescence microscopy. And PDS shows higher anti-ZIKV activity (EC50 = 4.2 ± 0.4 µM) than the other G-quadruplex binders as well as the positive control ribavirin, with a low cytotoxicity. By time-of-addition assay, PDS exerts antiviral activity at the post-entry process of ZIKV replication cycle, thus inhibiting ZIKV mRNA replication and protein expression. Furthermore, PDS combines with ZIKV NS2B-NS3 protease and reduces its catalytic activity. This study suggests that G-quadruplex binder PDS is an effective multi-target ZIKV inhibitor, which provides more guidance to design some novel anti-ZIKV drugs targeting ZIKV RNA G-quadruplexes.

Lanthanum and abscisic acid coregulate chlorophyll production of seedling in switchgrass.

The rare earth element lanthanum (La) has been proven to be beneficial for plant growth with a low concentration, and abscisic acid (ABA) which is a plant hormone also can regulate plant growth. In the present study, we investigated the germination and seedling growth of switchgrass (Panicum virgatum L.) under La (10 µM), ABA (10 µM) and La + ABA treatments. The results showed that La, ABA and La + ABA treatments could not significantly affect the germination and shoot length as compared to the control (P>0.05). However, La treatment increased the root activity and chlorophyll content, and ABA treatment enhanced root length and root activity (P<0.05). La + ABA treatments demonstrated that La could not significantly alleviate the promotion of ABA in root length, while ABA reversed the increase of chlorophyll content caused by La. The coregulation of La and ABA on chlorophyll content was further explored by in vitro experiments and quantum chemical calculations. In vitro experiments revealed that La, ABA, and La + ABA treatments reduced the absorbance of chlorophyll, and quantum chemical calculations indicated that the reduction of absorbance was caused by the reactions between La, ABA and chlorophyll. In vivo and in vitro experiments, together with quantum chemical calculations, demonstrated that both ABA and La could stimulate the production of chlorophyll, while they also could react with chlorophyll to produce La-monochlorophyll, La-bischlorophyll, and ABA adsorbed chlorophyll, which had lower absorbance. La + ABA treatment significantly decreased the chlorophyll content in vivo. This phenomenon was due to the fact that La and ABA formed LaABA compound, which markedly reduced the concentrations of ABA and La, and the effect of promoting chlorophyll production was overcome by the effect of reducing chlorophyll absorbance.

Novel technique for lymphadenectomy along left recurrent laryngeal nerve during thoracoscopic esophagectomy.

BACKGROUND: In esophageal squamous carcinoma, lymphadenectomy along the left recurrent laryngeal nerve (RLN) is recommended owing to its highly metastatic potential. However, this procedure is difficult due to limited working space in the left upper mediastinum, and increases postoperative complications. AIM: To present a novel method for lymphadenectomy along the left RLN during thoracoscopic esophagectomy in the semi-prone position. METHODS: The fundamental concept of this novel method is to exfoliate a bilateral pedicled nerve flap, which is a two-dimensional membrane, which includes the left RLN, lymph nodes (LNs) along the left RLN, and tracheoesophageal vessels, by suspending the esophagus to the dorsal side and pushing the trachea to the ventral side (named "bilateral exposure method"). Then, the hollow-out method is performed to transform the two-dimensional membrane to a three-dimensional structure, in which the left RLN and tracheoesophageal vessels are easily distinguished and preserved during lymphadenectomy along the left RLN. This novel method was retrospectively evaluated in 116 consecutive patients with esophageal squamous carcinoma from August 2016 to February 2018. RESULTS: There were 58 patients in each group. No significant difference was found between the two groups in terms of age, gender, postoperative pneumonia, anastomotic fistula, and postoperative hospitalization. However, the number of dissected LNs along the left RLN in this novel method was significantly higher than that in the conventional method (4.17 ± 0.359 vs 2.93 ± 0.463, P = 0.0447). Moreover, the operative time and the rate of postoperative hoarseness in the novel method were significantly lower than those in the conventional method (306.0 ± 6.774 vs 335.2 ± 7.750, P = 0.0054; 4/58 vs 12/58, P = 0.0312). CONCLUSION: This novel method for lymphadenectomy along the left RLN during thoracoscopic esophagectomy in the semi-prone position is much safer and more effective.

Systemic Therapy for Hepatocellular Carcinoma: Advances and Hopes.

The majority of patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage that can only benefit from systemic treatments. Although HCC is highly treatmentresistant, significant achievements have been made in the molecular targeted therapy and immunotherapy of HCC. In addition to regorafenib, cabozantinib and ramucirumab were approved for the second- line targeted treatment by the FDA after disease progression on sorafenib. Nivolumab failed to demonstrate remarkable benefit in overall survival (OS) as first-line therapy, while pembrolizumab did not achieve pre-specified statistical significance in both OS and progression-free survival (PFS) as second-line treatment. Combinations of targeted agents, immune checkpoint inhibitors and other interventions showed favorable results. In this review, we summarized the progress of systemic therapy in HCC and discussed the future directions of the treatment of HCC.