Integrated chromosomal instability and tumor microbiome redefined prognosis-related subtypes of pancreatic cancer.

BACKGROUND: Pancreatic cancer is a common malignancy with poor prognosis and limited treatment. Here we aimed to investigate the role of host chromosomal instability (CIN) and tumor microbiome in the prognosis of pancreatic cancer patients. METHODS: One hundred formalin-fixed paraffin-embedded (FFPE) pancreatic cancer samples were collected. DNA extracted from FFPE samples were analyzed by low-coverage whole-genome sequencing (WGS) via a customized bioinformatics workflow named ultrasensitive chromosomal aneuploidy detector. RESULTS: Samples are tested according to the procedure of ultrasensitive chromosomal aneuploidy detector (UCAD). We excluded 2 samples with failed quality control, 1 patient lost to follow-up and 6 dead in the perioperative period. The final 91 patients were admitted for the following analyses. Thirteen (14.3%) patients with higher CIN score had worse overall survival (OS) than those with lower CIN score. The top 20 microbes in pancreatic cancer samples included 15 species of bacteria and 5 species of viruses. Patients with high human herpesvirus (HHV)-7 and HHV-5 DNA reads exhibited worse OS. Furthermore, we classified 91 patients into 3 subtypes. Patients with higher CIN score (n =13) had the worst prognosis (median OS 6.9 mon); patients with lower CIN score but with HHV-7/5 DNA load (n = 24) had worse prognosis (median OS 10.6 mon); while patients with lower CIN score and HHV-7/5 DNA negative (n = 54) had the best prognosis (median OS 21.1 mon). CONCLUSIONS: High CIN and HHV-7/5 DNA load were associated with worse survival of pancreatic cancer. The novel molecular subtypes of pancreatic cancer based on CIN and microbiome had prognostic value.

Lopsided optical diffraction in a loop electromagnetically induced grating.

We propose a theoretical scheme in a cold rubidium-87 (87Rb) atomic ensemble with a non-Hermitian optical structure, in which a lopsided optical diffraction grating can be realized just with the combination of single spatially periodic modulation and loop-phase. Parity-time (PT) symmetric and parity-time antisymmetric (APT) modulation can be switched by adjusting different relative phases of the applied beams. Both PT symmetry and PT antisymmetry in our system are robust to the amplitudes of coupling fields, which allows optical response to be modulated precisely without symmetry breaking. Our scheme shows some nontrivial optical properties, such as lopsided diffraction, single-order diffraction, asymmetric Dammam-like diffraction, etc. Our work will benefit the development of versatile non-Hermitian/asymmetric optical devices.

Research progress in controllable proteolysis targeting chimeras / 药学学报

Proteolysis targeting chimeras (PROTACs) is an innovative technique in targeted protein degradation. PROTACs is a heterobifunctional molecule which can bind to the E3 ligase and target protein to form a ubiquitination complex, resulting in the ubiquitin-proteasome system dependent degradation of target protein. PROTACs has been regarded as the promising method in drug discovery campaign, for its high commonality, potent degradation activity and unique selectivity profile. However, the catalytic mechanism also induces the uncontrollable protein degradation risk. Controllable PROTACs contain the responsive element in the molecular entity. In certain conditions, the element can be triggered to activate or terminate the degradation event. In this review, we will briefly summarize the strategies in controllable PROTACs and describe the representative examples according to the responsive mechanism. We hope this review could provide some insight into the further development of controllable PROTACs.

Latissimus dorsi muscle flap transfer through endoscopic approach combined with the implant after tissue expansion for breast reconstruction of mastectomy patients.

BACKGROUND: Implant-based breast reconstruction is easy to be performed but has flaws that an unnatural appearance might be presented when no sufficient coverage existing. While autologous tissue reconstruction also has disadvantages like donor site scar and skin patch effect. There is a demand for a new method to obtain natural and aesthetic appearance while surmounting drawbacks of conventional breast reconstruction surgery. METHODS: A retrospective review of thirty-one patients undergoing tissue expander (TE)/implant two-stage breast reconstruction with latissimus dorsi muscle flap (LDMF) transfer through endoscopic approach in Peking University Third Hospital from April 2016 to August 2020 was performed. The LDMF harvest time, drain time, and complications were reviewed. The 3D volume was obtained to assess the volume symmetry of bilateral breasts. The BREAST-Q reconstruction module was used to evaluate the satisfaction. RESULTS: The mean endoscopic LDMF harvest time was 90.4 min. In the mean follow-up of 11.2 months, there were no severe capsular contracture happened. The reconstructed side achieved good volume symmetry to the contralateral side (P = 0.256). Based on the evaluation of the BREAST-Q scores, the outcome of Satisfaction with Breasts was excellent or good in 87.1% of the cases. CONCLUSIONS: The novel type of two-stage breast reconstruction protocol, which includes tissue expansion followed by implant insertion with endoscopy-assisted LDMF transfer, could effectively reduce visible scars, avoid the patch effect, while require short time for LDMF harvest and present low incidence of complications. It is a promising method for breast reconstruction because it achieves good outcomes in the mastectomy patients.

Research progress of Nrf2 inhibitor in tumor therapy / 药学学报

Nrf2 is a multi-effect transcription factor, which plays a crucial role in cytoprotective system. With the deepening of research on new regulatory modes and biologic functions of Nrf2, the oncogenic role of Nrf2 in malignant transformed tumors is increasingly obvious. More and more evidences show that Nrf2 is involved in the whole process of tumor occurrence, development, metastasis and prognosis, and inhibiting Nrf2 may be a promising strategy in tumor therapy. However, the development of Nrf2 inhibitors is still in early stage. In this paper, the biological function of Nrf2 and its dual role in tumor are briefly introduced, and representative Nrf2 inhibitors are reviewed according to their structure types, so as to provide reference and ideas for the development of anti-tumor drugs centering on the regulation of Nrf2.

HPV Prevalence and Genotype Distribution Among Women From Hengyang District of Hunan Province, China.

Most cervical cancers were closely associated with human papillomavirus (HPV) infections. Therefore, understanding the ecological diversity of HPV prevalence and genotype distribution among various populations in different geographical regions was essential for optimizing HPV vaccination and maximizing the vaccination effects. A total of 12,053 patient data from the three-level hospitals in Hengyang city were retrospectively analyzed. In this study, the HPV prevalence was 10.16% overall, and the multiple-type infection rate was 1.83%. The HR-HPV infection rate was 8.52%. The top six HPV genotypes were as follows in descending order: HPV16, HPV58, HPV52, HPV39, HPV51, and HPV53. The HPV prevalence in the group above 60 years old was the most, and their HR-HPV infection rate corresponded to the most too. The infection rates of HPV and HR-HPV among outpatients were both lower than those among the hospitalized-patients, respectively. Among the hospitalized-patients, the infection rates of HPV and HR-HPV among the 50-60 years group were the most in both. The HR-HPV ratio-in-positive among HPV-positive patients with the histopathologic examination was higher than that among those patients without. Among 52 HPV-positive patients with cervical squamous carcinoma, the ratio-in-positive of HPV16 was 61.54%. This study demonstrated that the HPV prevalence varied with age among women from Hengyang district of Hunan province in China and showed that HPV16, HPV58, HPV52, HPV39, HPV51, and HPV53 genotypes were more popularly distributed in this region, which could provide the experimental basis for Chinese public health measures on cervical cancer prevention.

Nomogram to predict primary non-response to infliximab in patients with Crohn's disease: a multicenter study.

BACKGROUND: Infliximab (IFX) is effective at inducing and maintaining clinical remission and mucosal healing in patients with Crohn's disease (CD); however, 9%-40% of patients do not respond to primary IFX treatment. This study aimed to construct and validate nomograms to predict IFX response in CD patients. METHODS: A total of 343 patients diagnosed with CD who had received IFX induction from four tertiary centers between September 2008 and September 2019 were enrolled in this study and randomly classified into a training cohort (n = 240) and a validation cohort (n = 103). The primary outcome was primary non-response (PNR) and the secondary outcome was mucosal healing (MH). Nomograms were constructed from the training cohort using multivariate logistic regression. Performance of nomograms was evaluated by area under the receiver-operating characteristic curve (AUC) and calibration curve. The clinical usefulness of nomograms was evaluated by decision-curve analysis. RESULTS: The nomogram for PNR was developed based on four independent predictors: age, C-reactive protein (CRP) at week 2, body mass index, and non-stricturing, non-penetrating behavior (B1). AUC was 0.77 in the training cohort and 0.76 in the validation cohort. The nomogram for MH included four independent factors: baseline Crohn's Disease Endoscopic Index of Severity, CRP at week 2, B1, and disease duration. AUC was 0.79 and 0.72 in the training and validation cohorts, respectively. The two nomograms showed good calibration in both cohorts and were superior to single factors and an existing matrix model. The decision curve indicated the clinical usefulness of the PNR nomogram. CONCLUSIONS: We established and validated nomograms for the prediction of PNR to IFX and MH in CD patients. This graphical tool is easy to use and will assist physicians in therapeutic decision-making.

Identification of a new azoreductase driven prodrug from bardoxolone methyl and 5-aminosalicylate for the treatment of colitis in mice / 中国天然药物

For local treatment of ulcerative colitis, a new azoreductase driven prodrug CDDO-AZO from bardoxolone methyl (CDDO-Me) and 5-aminosalicylate (5-ASA) was designed, synthesized and biologically evaluated. It is proposed that orally administrated CDDO-AZO is stable before reaching the colon, while it can also be triggered by the presence of azoreductase in the colon to fragment into CDDO-Me and 5-ASA, generating potent anti-colitis effects. Superior to olsalazine (OLS, a clinically used drug for ulcerative colitis) and CDDO-Me plus 5-ASA, CDDO-AZO significantly attenuated inflammatory colitis symptoms in DSS-induced chronic colitis mice, which suggested that CDDO-AZO may be a promising anti-ulcerative colitis agent.

The role of MYB proto-oncogene like 2 in tamoxifen resistance in breast cancer.

Despite the efficacy of tamoxifen in preventing disease relapse, a large portion of breast cancer patients show intrinsic or acquired resistance to tamoxifen, leading to treatment failure and unfavorable clinical outcome. MYB proto-oncogene like 2 (MYBL2) is a transcription factor implicated in the initiation and progression of various human cancers. However, its role in tamoxifen resistance in breast cancer remained largely unknown. In the present study, by analyzing public transcriptome dataset, we found that MYBL2 is overexpressed in breast cancer and is associated with the poor prognosis of breast cancer patients. By establishing tamoxifen-resistant breast cancer cell lines, we also provided evidence that MYBL2 overexpression contributes to tamoxifen resistance by up-regulating its downstream transcriptional effectors involved in cell proliferation (PLK1, PRC1), survival (BIRC5) and metastasis (HMMR). In contrast, inhibiting those genes via MYBL2 depletion suppresses cancer progression, restores tamoxifen and eventually reduces the risk of disease recurrence. All these findings revealed a critical role of MYBL2 in promoting tamoxifen resistance and exacerbating the progression of breast cancer, which may serve as a novel therapeutic target to overcome drug resistance and improve the prognosis of breast cancer patients.

Dual-gate transistor amplifier in a multimode optomechanical system.

We present a dual-gate optical transistor based on a multimode optomechanical system, composed of three indirectly coupled cavities and an intermediate mechanical resonator pumped by a frequency-matched field. In this system, two cavities driven on the red mechanical sidebands are regarded as input/ouput gates/poles and the third one on the blue sideband as a basic/control gate/pole, while the resonator as the other basic/control gate/pole. As a nonreciprocal scheme, the significant unidirectional amplification can be resulted by controlling the two control gates/poles. In particular, the nonreciprocal direction of the optical amplification/rectification can be controlled by adjusting the phase differences between two red-sideband driving fields (the pumping and probe fields). Meanwhile, the narrow window that can be analyzed by the effective mechanical damping rate, arises from the extra blue-sideband cavity. Moreover, the tunable slow/fast light effect can be observed, i.e, the group velocity of the unidirectional transmission can be controlled, and thus the switching scheme of slow/fast light effect can also utilized to realize both slow and fast lights through opposite propagation directions, respectively. Such an amplification transistor scheme of controllable amplitude, direction and velocity may imply exciting opportunities for potential applications in photon networks and quantum information processing.

Advances in anti-tumor drug research based on reactive oxygen regulation / 药学学报

Reactive oxygen species (ROS) which were partial metabolites of oxygen are highly reactive. Different concentrations of ROS have different effects on tumor development. Tumor cells have a high level of reactive oxygen species. The antioxidant system of tumor is in highly activated state, and thus modulation of reactive oxygen species levels could be an effective strategy to target cancer cells. Treatment with small molecules that disrupt the redox balance can kill tumor cells first. This paper outlines the main ideas of developing anti-tumor drugs based on reactive oxygen species regulation, and summarizes the representative drugs and research progress according to the mechanism of action, in an effort to suggest potential reference and ideas for developing anti-tumor drugs based on reactive oxygen species regulation.

The mpn668 gene of Mycoplasma pneumoniae encodes a novel organic hydroperoxide resistance protein.

Mycoplasma pneumoniae (M. pneumoniae), as an obligate parasite, has evolved a protective strategy for coping with oxidative challenges caused by M. pneumoniae itself as well as the host immune system. However, to date, few antioxidant enzymes have been identified in mycoplasmas. In this report, we identified a protein encoded by the mpn668 gene from M. pneumoniae with a putative function as an organic hydroperoxide reductase (Ohr). The results indicated that the recombinant 140 amino acid protein, designated rMPN668, displayed hydroperoxidase activity towards both organic (tert-butyl hydroperoxide) and inorganic (hydrogen peroxide) hydroperoxides in the presence of a reducing agent such as dithiothreitol. Moreover, the expression of mpn668 in M. pneumoniae is upregulated in response to oxidative stress. Additionally, homology modeling of MPN668 and a molecular dynamics simulation suggest that both Cys55 and Cys119 form part of the active site of the protein. Mutants in which Cys55 or Cys119 were replaced with a serine lack antioxidant activity, indicating that MPN668 is a Cys-based peroxidase, consistent with it representing a new member of the Ohr family.

All-optical transistor based on Rydberg atom-assisted optomechanical system.

We study the optical response of a double optomechanical cavity system assisted by two Rydberg atoms. The target atom is only coupled with one side cavity by a single cavity mode, and gate one is outside the cavities. It has been realized that a long-range manipulation of optical properties of a hybrid system, by controlling the Rydberg atom decoupled with the optomechanical cavity. Switching on the coupling between atoms and cavity mode, the original spatial inversion symmetry of the double cavity structure has been broken. Combining the controllable optical non-reciprocity with the coherent perfect absorption/transmission/synthesis effect (CPA/CPT/CPS reported by [ X.-B.Yan Opt. Express 22, 4886 (2014)], we put forward the theoretical schemes of an all-optical transistor which contains functions such as a controllable diode, rectifier, and amplifier by controlling a single gate photon.

Enhanced nonlinear characteristics with the assistance of a [Formula: see text]-symmetric trimer system.

We study the parity-time (PT) symmetry characteristics and the applications to nonlinear optics in an optical trimer system consisting of two indirectly coupled standing-mode micro-cavities and a two-level quantum emitter (QE) placed at the intersection of two cavities. We find this trimer system can exhibit analogical phenomena as those in typical [Formula: see text]-symmetric dimer systems composed of a passive cavity directly coupled to an active cavity. This system, whose [Formula: see text] symmetry is demonstrated by our analytic results, can be transformed between the [Formula: see text]-symmetric phase and the [Formula: see text]-broken phase by adjusting relevant system parameters. Then, with this system, we observe both the linear and nonlinear parts of the transmission field become remarkably enhanced and can further reach peak values around the [Formula: see text] breaking point. In addition, we show the negative correlation between the gain degree of the linear (nonlinear) transmission part and decay rate of the QE. This trimer proposal is feasible for experiments and may provide a promising platform for [Formula: see text]-symmetric optics of low-light levels. Moreover, novel phenomena arising from the QE-cavity-coupling induced nonlinearity gain could be explored to fabricate photonic devices and controllable nonlinear optical media for quantum information process and communication of photons.

Intrinsic link of asymmetric reflection and diffraction in non-Hermitian gratings.

Asymmetric reflection in Bragg gratings and asymmetric diffraction in diffraction gratings are both linked to parity-time (PT) symmetry in non-Hermitian optics, but their direct relation has not been examined. To fill this gap, we first consider a PT-symmetric sinusoidal grating to compare the contrast of forward and backward reflectivities and the ratio of ±1-order diffraction efficiencies. Analytical and numerical results show that they change with identical tendencies and peaks at same positions in a wide parameter space, indicating thus an intrinsic link in both PT symmetric and PT broken phases. The underlying physics is found to be that the unbalanced coupling strengths between forward and backward reflected waves are identical to those between 0-order and ±1-order diffracted waves. We then consider a non-Hermitian grating dynamically induced in cold atomic lattices to include higher-order diffractions and corresponding reflections.Full numerical calculations show that the aforementioned findings hold also true in this complicated but practical grating, even in more general non-Hermitian cases beyond the exact PT symmetry.

Experimental research on individual-specific rapid potassium supplementation strategy for fatal severe hypokalemia / 中华危重病急救医学

Objective To explore the effectiveness and safety of the individual-specific rapid potassium supplementation strategy, and to provide experimental basis for treating fatal severe hypokalemia. Methods An acute fatal severe hypokalemia model was reproduced in 20 healthy adult Japanese big ear white rabbits with half lethal dose (LD50) of barium chloride (BaCl2) solution 168 mg·5 mL-1·kg-1. The rabbits were divided into conventional potassium supplementation group and individual-specific rapid potassium supplementation group according to random number table method with 10 rabbits in each group. All the animals were injected with 3% KCl through the auricular marginal veins by a micro-injection pump, and the target plasma potassium concentration was 4 mmol/L. The rabbits in conventional potassium supplementation group were administered continuously potassium infusion at the standard infusion rate of 0.4 mmol·kg-1·h-1. And those in the individual-specific rapid potassium supplementation group were treated in two steps: first, a loading dose of potassium was rapidly injected within 5 minutes, and this step was repeated until the plasma potassium concentration increased to 3.5 mmol/L; second, a sustaining dose of potassium infusion was continued at the rate of 0.4 mmol·kg-1·h-1 after the increase in plasma potassium concentration. The changes in electrocardiogram, blood pressure, respiratory rate (RR), plasma potassium concentration, urine potassium concentration, urine volume, potassium content in extracellular fluid (ECF) and other parameters were monitored. The potassium supplementation, potassium excretion and potassium cross cell status were recorded. Adverse reactions and 7-day death were observed. Results Since the BaCl2 administration, the plasma potassium concentration of all experimental rabbits were significantly lower than baseline at 0.5 hour, which was decreased below 2.5 mmol/L at 2.0 hours when the ventricular arrhythmias appeared, indicating the reproduction of fatal severe hypokalemia model was successful. There was no significant difference in gender, weight, baseline heart rate (HR), RR, mean arterial pressure (MAP), blood gas analysis or K+, Na+, Cl- levels between the two groups. Compared with baseline levels, MAP was significantly decreased and RR was significantly increased before potassium supplementation in both groups, but the parameters were improved significantly and restored to the baseline after potassium supplementation. There was no significant difference in MAP or RR during potassium supplementation between the two groups. The amount of potassium supplementation in two groups showed no significant differences. However, compared with the conventional potassium supplementation group, in the individual-specific rapid potassium supplementation group, the increase in plasma potassium concentration, urine potassium concentration, and the increase in potassium content in ECF were significantly increased [the increase in plasma potassium concentration (mmol/L): 2.40±0.33 vs. 1.51±0.75, urine potassium concentration (mmol/L):164.94±18.07 vs. 108.35±19.67, the increase in potassium content in ECF (mmol): 1.17±0.16 vs. 0.73±0.35], the duration of potassium infusion was shortened (hours: 2.1±0.7 vs. 4.7±1.4), the total urine volume, renal excretion of potassium, and the amount of transcellular potassium shift were significantly decreased [total urine volume (mL):6.40±1.78 vs. 13.60±4.69, renal excretion of potassium (mmol): 1.04±0.26 vs. 1.46±0.51, amount of transcellular potassium shift (mmol): 1.39±0.21 vs. 1.84±0.62], the duration of arrhythmia was shortened (minutes: 19.60±8.92 vs. 71.80±9.84), with statistically significant differences (all P < 0.05). Hyperkalemia did not occur in both groups. The rabbits of the individual-specific rapid potassium supplementation group were all alive, while 4 died in the conventional potassium supplementation group, and statistically significant difference was found between the two groups (P < 0.01). Conclusions These data demonstrate that the individual-specific rapid potassium supplementation strategy can shorten the time for correcting hypokalemia, which is a better option to reverse life-threatening arrhythmia caused by severe hypokalemia, with a high rescue success rate. The process of potassium supplement is safe and effective.

Asymmetric light diffraction of an atomic grating with PT symmetry.

Cold atoms trapped in one-dimensional optical lattices and driven to the four-level N configuration are exploited for achieving an electromagnetically induced grating with parity-time-symmetry. This nontrivial grating exhibits unidirectional diffraction patterns, e.g., with incident probe photons diffracted into either negative or positive angles, depending on the sign relation between spatially modulated absorption and dispersion coefficients. Such asymmetric light diffraction is a result of the out-of-phase interplay of amplitude and phase modulations of transmission function and can be easily tuned via optical depth, probe detuning, pump Rabi frequencies, etc.

Hypothetical protein Cpn0423 triggers NOD2 activation and contributes to Chlamydia pneumoniae-mediated inflammation.

BACKGROUND: Chlamydia pneumoniae (C. pneumoniae) is pathogenic to humans, by causing pulmonary inflammation or bronchitis in both adolescents and young adults. However, the molecular signals linking C. pneumoniae components to inflammation remain elusive. This study was to investigate the effect of Chlamydia-specific Cpn0423 of C. pneumoniae on C. pneumoniae-mediated inflammation. RESULTS: Cpn0423 was detected outside of C. pneumoniae inclusions, which induced production of several cytokines including macrophage inflammatory protein-2 (MIP-2) and interleukins (ILs). Production of the Cpn0423-induced cytokines was markedly reduced in cells pretreated with NOD2-siRNA, but not with negative control oligonucleotides. Mice treated with Cpn0423 through intranasal administration exhibited pulmonary inflammation as evidenced by infiltration of inflammatory cells, increased inflammatory scores in the lung histology, recruitment of neutrophils and increased cytokines levels in the BALF. CONCLUSION: Cpn0423 could be sensed by NOD2, which was identified as an essential element in a pathway contributing to the development of C. pneumoniae -mediated inflammation.

Synthesis and evaluation of 2-cyano-3, 12-dioxooleana-1, 9(11)-en-28-oate-13β, 28-olide as a potent anti-inflammatory agent for intervention of LPS-induced acute lung injury / 中国天然药物

The present study was designed to synthesize 2-Cyano-3, 12-dioxooleana-1, 9(11)-en-28-oate-13β, 28-olide (1), a lactone derivative of oleanolic acid (OA) and evaluate its anti-inflammatory activity. Compound 1 significantly diminished nitric oxide (NO) production and down-regulated the mRNA expression of iNOS, COX-2, IL-6, IL-1β, and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Further in vivo studies in murine model of LPS-induced acute lung injury (ALI) showed that 1 possessed more potent protective effects than the well-known anti-inflammatory drug dexamethasone by inhibiting myeloperoxidase (MPO) activity, reducing total cells and neutrophils, and suppressing inflammatory cytokines expression, and thus ameliorating the histopathological conditions of the injured lung tissue. In conclusion, compound 1 could be developed as a promising anti-inflammatory agent for intervention of LPS-induced ALI.

Cooperative nonlinear grating sensitive to light intensity and photon correlation.

Utilizing dipole blockade of Rydberg excitations, we study an ensemble of stationary atoms driven into the four-level N configuration for achieving a new kind of electromagnetically induced grating in the presence of a traveling-wave and a standing-wave classical control fields. This grating shows cooperative optical nonlinearities as manifested by the sensitivity of output diffraction patterns to input light intensities (photon correlations) of a quantum probe field, promising then an essential opportunity for distinguishing weaker and stronger (bunched and anti-bunched) light fields.