Sensitization of hepatocellular carcinoma cells to HDACi is regulated through hsa-miR-342-5p/CFL1.

BACKGROUND: Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance. METHODS: MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro. RESULTS: Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner. CONCLUSION: Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.

Mediation of radiation-induced bystander effect and epigenetic modification: The role of exosomes in cancer radioresistance.

Exosomes are nano-sized extracellular vesicles produced by almost all mammalian cells. They play an important role in cell-to-cell communication by transferring biologically active molecules from the cell of origin to the recipient cells. Ionizing radiation influences exosome production and molecular cargo loading. In cancer management, ionizing radiation is a form of treatment that exerts its cancer cytotoxicity by induction of DNA damage and other alterations to the targeted tissue cells. However, normal bystander non-targeted cells may exhibit the effects of ionizing radiation, a phenomenon called radiation-induced bystander effect (RIBE). The mutual communication between the two groups of cells (targeted and non-targeted) via radiation-influenced exosomes enables the exchange of radiosensitive molecules. This facilitates indirect radiation exposure, leading, among other effects, to epigenetic remodeling and subsequent adaptation to radiation. This review discusses the role exosomes play in epigenetically induced radiotherapy resistance through the mediation of RIBE.

Realization of fractional quantum Hall state with interacting photons.

Fractional quantum Hall (FQH) states are known for their robust topological order and possess properties that are appealing for applications in fault-tolerant quantum computing. An engineered quantum platform would provide opportunities to operate FQH states without an external magnetic field and enhance local and coherent manipulation of these exotic states. We demonstrate a lattice version of photon FQH states using a programmable on-chip platform based on photon blockade and engineering gauge fields on a two-dimensional circuit quantum electrodynamics system. We observe the effective photon Lorentz force and butterfly spectrum in the artificial gauge field, a prerequisite for FQH states. After adiabatic assembly of Laughlin FQH wave function of 1/2 filling factor from localized photons, we observe strong density correlation and chiral topological flow among the FQH photons. We then verify the unique features of FQH states in response to external fields, including the incompressibility of generating quasiparticles and the smoking-gun signature of fractional quantum Hall conductivity. Our work illustrates a route to the creation and manipulation of novel strongly correlated topological quantum matter composed of photons and opens up possibilities for fault-tolerant quantum information devices.

Tannic Acid Impedes the Proliferation of Bladder Cancer Cells by Elevating Mitochondrial Pathways of Apoptosis.

Bladder cancer stands as a prevailing neoplasm among men globally, distinguished for its pronounced malignancy attributed to invasiveness and metastatic proclivity. Tannic acid (TA), an organic compound in many plants, has garnered recent attention for its discernible anti-mutagenic attributes. This investigation endeavored to scrutinize the repercussions of TA on grade II bladder cancer, with a concerted focus on unraveling its anti-cancer mechanisms. The cytotoxic effects of TA on grade II bladder cancer cells were investigated using multiple techniques, including MTT assay, flow cytometry, TUNEL assay, and western blot. Our findings revealed that elevated concentrations of TA induced cytotoxic effects in grade II bladder cancer cells. Both flow cytometry and the TUNEL assay substantiated the dose-dependent capacity of TA to prompt apoptosis. Western blot analysis corroborated that TA treatment in bladder cancer cells resulted in the upregulation of cleaved caspase-3 expression and PARP. Furthermore, heightened TA dosage elicited an augmentation in the expression of pro-apoptotic proteins, namely Bax and Bak, alongside a reduction in the expression of the anti-apoptotic protein Bcl-2 within bladder cancer cells. This study confirms TA as a potential anticancer agent, demonstrably diminishing the viability of bladder cancer cells. TA exerts cytotoxicity through the activation of mitochondrial apoptotic pathways. Specifically, TA initiates the cleavage of PARP and caspase-3, concurrently augmenting the expression of pro-apoptotic proteins to facilitate apoptosis. Collectively, the present study indicates that TA effectively impedes the proliferation of bladder cancer cells by instigating apoptosis through the intrinsic mitochondrial pathway.

Predicting the cryotolerance of boar sperm through antioxidant stress.

High sperm cryotolerance is crucial to the successful cryopreservation of boar sperm. Evaluating the cryotolerance of boar sperm by using a rapid and convenient technique can enhance the commercial viability of these sperm. This study investigated the correlation between sperm parameters for three sample subsets-fresh sperm, sperm with H2O2-induced oxidative damage (hereinafter referred to as H2O2-induced sperm), and frozen-thawed sperm-to identify the potential of these correlations to predict cryotolerance. A total of 64 sperm samples were obtained from 64 Duroc boars. The sperm parameters of the three subsets, where the frozen-thawed sperm were analysed at 30 or 180 min after thawing, were determined, and the coefficients of correlation between these parameters were calculated. The results indicated that H2O2-induced oxidative stress resulted in decreases in various sperm parameters-including total motility (TM), viability (VIA), mitochondrial membrane potential (MMP), and live sperm with MMP (LMP)-but increased their coefficients of variation. Receiver operating characteristic (ROC) curve analysis revealed that the kinematic parameters of the H2O2-induced sperm effectively predicted those of the frozen-thawed boar sperm at 30 min after thawing; the corresponding area under the ROC curve (AUC) was 0.8667 for TM and 0.8733 for progressive motility in the H2O2-induced sperm. For measurement at 180 min after thawing, the sperm membrane and mitochondrial parameters of the H2O2-induced sperm effectively predicted the LMP of the frozen-thawed boar sperm; the corresponding AUC was 0.8489 for VIA, 0.8289 for MMP, and 0.8444 for LMP. To our knowledge, this is the first study to directly establish a strong correlation between post-thaw boar sperm quality and H2O2-induced oxidative stress before freezing. Our proposed technique can serve as a valuable reference for the development of practical applications aimed at enhancing techniques for cryopreserving boar sperm.

Novel chromium (III)-based compound for inhibition of oxaliplatin-resistant colorectal cancer progression.

Colorectal cancer (CRC) ranks as the third leading cause of cancer-related mortality worldwide. The current standard of care includes systemic chemotherapy with cytotoxic agents, offering palliative relief for severe CRC cases and serving as the primary therapy for metastatic recurrence. However, the development of chemoresistance poses a substantial obstacle in the realm of chemotherapy. This study delved into the potential of a novel chromium (III)-based compound, hexaacetotetraaquadihydroxochromium (III) diiron (III) nitrate, for CRC treatment. The therapeutic promise of this innovative chromium (III)-based compound was explored by utilizing LoVo colon cancer cells and an in-vivo mouse model of CRC. Various dosages of the compound were administered to LoVo parental cells and LoVo oxaliplatin-resistant cells. Findings unveiled that a concentration of 2000 µg/mL of the chromium (III) compound significantly inhibited mesenchymal transition and the migratory and invasive properties of LoVo oxaliplatin-resistant cells. This novel chromium (III)-based compound also demonstrated similar efficacy in other different CRC cell lines. The tumor growth was in the in-vivo mouse model was reduced by this compound. Moreover, the chromium (III)-based compound induced apoptosis by triggering the endoplasmic reticulum (ER) stress pathway in LoVo oxaliplatin-resistant cells. This study illuminates the capacity of the novel chromium (III)-based compound to impede the progression and growth of chemotherapy-resistant CRC. This discovery instills confidence in the potential of this compound as a therapeutic agent for CRC, even in the face of drug resistance. It holds the promise of serving as a valuable asset in the future treatment of chemotherapy-resistant CRC.

Aloin and CPT-11 combination activates miRNA-133b and downregulates IGF1R- PI3K/AKT/mTOR and MEK/ERK pathways to inhibit colorectal cancer progression.

CPT-11 is one of the drugs employed in colorectal cancer treatment and has faced challenges in the form of resistance. The insulin-like growth factor 1 receptor is a tyrosine kinase receptor that mediates cancer cell survival and drug resistance. It is frequently overexpressed in colorectal cancer and has previously been identified as a microRNA target. MicroRNAs are non-coding RNA molecules that regulate gene function by suppressing messenger RNA translation. Studies have demonstrated that natural compounds can regulate microRNA function and their target genes. Therefore, combining natural compounds with existing cancer drugs can enhance the therapeutic efficacy. We investigated a natural compound, Aloin, for the potential sensitization of colorectal cancer to CPT-11. We used western blot, MTT cell viability assay, flow cytometry, and microRNA/gene knockdown and overexpression experiments, as well as an in vivo mouse model. Our investigation revealed that combining Aloin with CPT-11 exerts an enhanced anti-tumor effect in colorectal cancer. This combination reduced cell viability and induced apoptosis, both in vivo and in vitro. Furthermore, this combination upregulated miRNA-133b, while downregulating the IGF1R and its downstream MEK/ERK, and PI3K/AKT/mTOR pathways. Our findings suggests that CPT-11 and Aloin are potential combination treatment partners against colorectal cancer. MicroRNA-133b may serve as a co-therapeutic target with IGF1R against colorectal cancer, which might overcome the existing treatment limitations.

Gaussian Boson Sampling with Pseudo-Photon-Number-Resolving Detectors and Quantum Computational Advantage.

We report new Gaussian boson sampling experiments with pseudo-photon-number-resolving detection, which register up to 255 photon-click events. We consider partial photon distinguishability and develop a more complete model for the characterization of the noisy Gaussian boson sampling. In the quantum computational advantage regime, we use Bayesian tests and correlation function analysis to validate the samples against all current classical spoofing mockups. Estimating with the best classical algorithms to date, generating a single ideal sample from the same distribution on the supercomputer Frontier would take ∼600 yr using exact methods, whereas our quantum computer, Jiǔzhang 3.0, takes only 1.27 µs to produce a sample. Generating the hardest sample from the experiment using an exact algorithm would take Frontier∼3.1×10^{10} yr.

Gemcitabine resistance in non-small cell lung cancer is mediated through activation of the PI3K/AKT/NF-κB pathway and suppression of ERK signaling by reactive oxygen species.

Lung cancer is one of the most common cancers in the world. Chemotherapy is a standard clinical treatment. However, tumor cells often develop multidrug resistance after chemotherapy, an inevitable bottleneck in cancer treatment. Therefore, this study used gemcitabine-resistant (GEM-R) CL1-0 lung cancer cells. First, we used flow cytometry and western blot analysis to examine differences in performance between resistant and parental cells. The results showed that compared with parental cells, GEM-R CL1-0 cells significantly enhanced the activation of the AKT pathway, which promoted survival and growth, and decreased the activation of the reactive oxygen species-extracellular signal-regulated kinase (ROS)-ERK pathway. Next, the AKT and ERK pathways' role in tumor growth was further explored in vivo using a xenograft model. The results showed that enhancing AKT and inhibiting ERK activation reduced GEM-induced inhibition of tumor growth. Finally, combining the above results, we found that GEM-R CL1-0 cells showed reduced sensitivity to GEM by activating the phosphatidylinositol 3-kinase/AKT/NF-kB pathway and inhibiting the ROS-ERK pathway leading to resistance against GEM. Therefore, the AKT and ERK pathways are potential targets for improving the sensitivity of cancer cells to anticancer drugs.

Calycosin inhibits gemcitabine-resistant lung cancer cells proliferation through modulation of the LDOC1/GNL3L/NFκB.

Lung cancer is the most common malignant cancer worldwide. Combination therapies are urgently needed to increase patient survival. Calycosin is a phytoestrogen isoflavone that has been reported previously to inhibit tumor cell growth, although its effects on lung cancer remain unclear. The aim of this study was to investigate the effects of calycosin on cell proliferation and apoptosis of gemcitabine-resistant lung cancer cells. Using calycosin to treat human lung cancer cells (CL1-0) and gemcitabine-resistant lung cancer cells (CL1-0 GEMR) and examine the effects on the cells. Cultured human lung cancer cells (CL1-0) and gemcitabine-resistant lung cancer cells (CL1-0 GEMR) were treated with increasing concentrations of calycosin. Cell viability and apoptosis were studied by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, flow cytometry, and TUNEL assays. Western blots were used to measure the expression levels of proliferation-related proteins and cancer stem cell proteins in CL1-0 GEMR cells. The results showed that calycosin treatment inhibited cell proliferation, decreased cell migration ability, and suppressed cancer stem cell properties in CL1-0 GEMR cells. Interestingly, in CL1-0 GEMR cells, calycosin treatment not only increased LDOC1 but also decreased GNL3L/NFκB protein levels and mRNA levels, in concentration-dependent manners. We speculate that calycosin inhibited cell proliferation of the gemcitabine-resistant cell line through regulating the LDOC1/GNL3L/NFκB pathway.

9-POHSA prevents NF-kB activation and ameliorates LPS-induced inflammation in rat hepatocytes.

Liver inflammation has become increasingly prevalent in recent years, leading to the development of diseases like hepatitis, alcoholic liver disease, and fatty liver disease. One factor that has been linked to liver inflammation is increased levels of lipopolysaccharides (LPS), which can be caused by poor diets and sedentary lifestyles that contribute to liver inflammation. There is promising research on a new class of lipids called fatty acid esters of hydroxy fatty acids (FAHFAs), which have been shown to potentiate insulin release and exert an anti-inflammatory effect. Specifically, one type of FAHFA called 9-POHSA (palmitoleic acid ester of 9-hydroxy stearic acid) has been studied for its potential to attenuate inflammation-related indexes induced by LPS in hepatocytes, which play a critical role in the progression of liver inflammation. This study found that following LPS treatment, tumor necrosis factor- α, interleukin-6, and connective tissue growth factor (CTGF) were upregulated and increased cell migration, but 9-POHSA pre-treatment attenuated the upregulation of these markers and prevented cell migration induced by LPS. Using flowcytometry analysis, intracellular reactive oxygen species (ROS) was found to be responsible for CTGF upregulation. In addition, the effects of 9-POHSA were likely associated with its inhibition of the activation of the NF-kB. These results suggest that 9-POHSA has potential as a therapy for liver inflammation and fibrosis by attenuating inflammation-related indexes induced by LPS in hepatocytes. This study provides important insight into the mechanisms of liver inflammation and the potential for new treatments to address liver diseases.

Schrödinger-Heisenberg Variational Quantum Algorithms.

Recent breakthroughs have opened the possibility of intermediate-scale quantum computing with tens to hundreds of qubits, and shown the potential for solving classical challenging problems, such as in chemistry and condensed matter physics. However, the high accuracy needed to surpass classical computers poses a critical demand on the circuit depth, which is severely limited by the non-negligible gate infidelity, currently around 0.1%-1%. The limited circuit depth places restrictions on the performance of variational quantum algorithms (VQA) and prevents VQAs from exploring desired nontrivial quantum states. To resolve this problem, we propose a paradigm of Schrödinger-Heisenberg variational quantum algorithms (SHVQA). Using SHVQA, the expectation values of operators on states that require very deep circuits to prepare can now be efficiently measured by rather shallow circuits. The idea is to incorporate a virtual Heisenberg circuit, which acts effectively on the measurement observables, into a real shallow Schrödinger circuit, which is implemented realistically on the quantum hardware. We choose a Clifford virtual circuit, whose effect on the Hamiltonian can be seen as efficient classical processing. Yet, it greatly enlarges the state's expressivity, realizing much larger unitary t designs. Our method enables accurate quantum simulation and computation that otherwise are only achievable with much deeper circuits or more accurate operations conventionally. This has been verified in our numerical experiments for a better approximation of random states, higher-fidelity solutions to the XXZ model, and the electronic structure Hamiltonians of small molecules. Thus, together with effective quantum error mitigation, our work paves the way for realizing accurate quantum computing algorithms with near-term quantum devices.

Ligustrazine improves the compensative effect of Akt survival signaling to protect liver Kupffer cells in trauma-hemorrhagic shock rats.

Trauma-hemorrhagic shock (THS) is a medical emergency that is encountered by physicians in the emergency department. Chuan Xiong is a traditional Chinese medicine and ligustrazine is a natural compound from it. Ligustrazine improves coronary blood flow and reduces cardiac ischemia in animals through Ca2+ and ATP-dependent vascular relaxation. It also decreases the platelets' bioactivity and reduces reactive oxygen species formation. We hypothesized that ligustrazine could protect liver by decreasing the inflammation response, protein production, and apoptosis in THS rats. Ligustrazine at doses of 100 and 1000 µg/mL was administrated in Kupffer cells isolated from THS rats. The protein expressions were detected via western blot. The THS showed increased inflammation response proteins, mitochondria-dependent apoptosis proteins, and had a compensation effect on the Akt pathway. After ligustrazine treatment, the hemorrhagic shock Kupffer cells decreased inflammatory response and mitochondria-dependent apoptosis and promoted a more compensative effect of the Akt pathway. It suggests ligustrazine reduces inflammation response and mitochondria-dependent apoptosis induced by THS in liver Kupffer cells and promotes more survival effects by elevating the Akt pathway. These findings demonstrate the beneficial effects of ligustrazine against THS-induced hepatic injury, and ligustrazine could be a potential medication to treat the liver injury caused by THS.

Quantum computer-aided design for advanced superconducting qubit: Plasmonium.

Complex quantum electronic circuits can be used to design noise-protected qubits, but their complexity may exceed the capabilities of classical simulation. In such cases, quantum computers are necessary for efficient simulation. In this work, we demonstrate the use of variational quantum computing on a transmon-based quantum processor to simulate a superconducting quantum electronic circuit and design a new type of qubit called "Plasmonium", which operates in the plasmon-transition regime. The fabricated Plasmonium qubits show a high two-qubit gate fidelity of 99.58(3)%, as well as a smaller physical size and larger anharmonicity compared to transmon qubits. These properties make Plasmonium a promising candidate for scaling up multi-qubit devices. Our results demonstrate the potential of using quantum computers to aid in the design of advanced quantum processors.

Phosphorylation of Bcl-2 by JNK confers gemcitabine resistance in lung cancer cells by reducing autophagy-mediated cell death.

The most common cancer-related death in the world is non-small cell lung cancer (NSCLC). Gemcitabine (GEM) is a common and effective first-line chemotherapeutic drug for the treatment of NSCLC. However, the long-term use of chemotherapeutic drugs in patients usually induces cancer cell drug resistance, leading to poor survival, and prognosis. In this study, to observe and explore the key targets and potential mechanisms of NSCLC resistance to GEM, we first cultured lung cancer CL1-0 cells in a GEM-containing medium to induce CL1-0 cells to develop GEM resistance. Next, we compared protein expression between the parental and GEM-R CL1-0 cell groups. We observed significantly lower expression of autophagy-related proteins in GEM-R CL1-0 cells than in parental CL1-0 cells, indicating that autophagy is associated with GEM resistance in CL1-0 cells. Furthermore, a series of autophagy experiments revealed that GEM-R CL1-0 cells had significantly reduced GEM-induced c-Jun N-terminal kinase phosphorylation, which further affected the phosphorylation of Bcl-2, thereby reducing the dissociation of Bcl-2 and Beclin-1 and ultimately reducing the generation of GEM-induced autophagy-dependent cell death. Our findings suggest that altering the expression of autophagy is a promising therapeutic option for drug-resistant lung cancer.

Experimental Full Network Nonlocality with Independent Sources and Strict Locality Constraints.

Nonlocality arising in networks composed of several independent sources gives rise to phenomena radically different from that in standard Bell scenarios. Over the years, the phenomenon of network nonlocality in the entanglement-swapping scenario has been well investigated and demonstrated. However, it is known that violations of the so-called bilocality inequality used in previous experimental demonstrations cannot be used to certify the nonclassicality of their sources. This has put forward a stronger concept for nonlocality in networks, called full network nonlocality. Here, we experimentally observe full network nonlocal correlations in a network where the source-independence, locality, and measurement-independence loopholes are closed. This is ensured by employing two independent sources, rapid setting generation, and spacelike separations of relevant events. Our experiment violates known inequalities characterizing nonfull network nonlocal correlations by over 5 standard deviations, certifying the absence of classical sources in the realization.

Solving Graph Problems Using Gaussian Boson Sampling.

Gaussian boson sampling (GBS) is not only a feasible protocol for demonstrating quantum computational advantage, but also mathematically associated with certain graph-related and quantum chemistry problems. In particular, it is proposed that the generated samples from the GBS could be harnessed to enhance the classical stochastic algorithms in searching some graph features. Here, we use Jiǔzhang, a noisy intermediate-scale quantum computer, to solve graph problems. The samples are generated from a 144-mode fully connected photonic processor, with photon click up to 80 in the quantum computational advantage regime. We investigate the open question of whether the GBS enhancement over the classical stochastic algorithms persists-and how it scales-with an increasing system size on noisy quantum devices in the computationally interesting regime. We experimentally observe the presence of GBS enhancement with a large photon-click number and a robustness of the enhancement under certain noise. Our work is a step toward testing real-world problems using the existing noisy intermediate-scale quantum computers and hopes to stimulate the development of more efficient classical and quantum-inspired algorithms.

Developing a Robotic Surgical Platform Is Beneficial to the Implementation of the ERAS Program for Colorectal Surgery: An Outcome and Learning Curve Analysis.

BACKGROUND: Robotic surgery and ERAS protocol care are both prominent developments and have each become global trends. However, the effects and learning curves of combining robotic surgery and ERAS care in colorectal resection have not yet been well validated. This study aimed to present our real-world experience and establish the learning curves necessary for the implementation of an ERAS program in minimally-invasive surgery for colorectal resection, while also evaluating the impact that the development of the robotic technique has on ERAS outcomes. METHODS: A total of 155 patients who received elective, minimally-invasive surgery, including laparoscopic and robotic surgery for colorectal resection, with ERAS care during the period June 2019 to September 2021 were included in this retrospective analysis. Patients were divided chronologically into five groups (31 cases per quintile). Patient demographics, tumor characteristics, perioperative data, ERAS compliance, and surgical outcomes were all compared among the quintiles. Learning curves were evaluated based on ERAS compliance and optimal recovery, which are composed of an absence of major complications, postoperative length of stay (LOS) of no more than five days, and no readmission within 30 days. A multivariable logistic regression model was used to assess factors associated with postoperative LOS. RESULTS: There were no statistically significant differences seen overall or between the quintile groups in regards to demographic and tumor characteristic parameters. A total of 79 patients (51%) received robotic surgery, with the ratio of robotic groups rising chronologically from zero in the first quintile to 90.3% in the fifth quintile (p < 0.001). The median compliance rate of total ERAS protocol was 83.3% overall, 72.2% in the first quintile and 83.3% in the 2nd-5th quintiles (p < 0.001). A total of 85 patients underwent optimal recovery after surgery, four patients in the first quintile, 11 patients in the second quintile, and 21, 24, 25 patients in the 3rd-5th quintiles respectively (p < 0.001). There were significant improvements from early to later groups upon postoperative LOS (p < 0.001). In addition, the surgical outcomes including first oral intake within 24 hours after surgery, time to first stool and early termination of intravenous fluid administration showed significant improvement among the quintiles. A multivariable logistic regression model demonstrated that robotic surgery was superior to laparoscopic surgery upon postoperative LOS (odds ratio = 5.029, 95% confidence interval [CI] = 1.321 to 19.142; p = 0.018). CONCLUSIONS: Our experience demonstrated that an effective implementation of the ERAS program in minimally-invasive colorectal surgery requires 31 patients to accomplish the higher compliance and requires more cases to reach the maturation phase for optimal recovery. We believe that developing a robotic platform would have no impact on the learning curve of ERAS implementation. Moreover, there is a beneficial effect on the postoperative length of surgery provided through the combination of ERAS care and robotic surgery for patients undergoing colorectal resection.

Platycodin D confers oxaliplatin Resistance in Colorectal Cancer by activating the LATS2/YAP1 axis of the hippo signaling pathway.

Oxaliplatin-based therapy is used as a first-line drug to treat metastatic colorectal cancer. However, long-term and repeated drug treatment resulted in drug resistance and the failure of chemotherapy. Various natural compounds were previously reported to act as chemosensitizers to reverse drug resistance. In this study, we found that platycodin D (PD), a saponin found in Platycodon grandiflorum, inhibited LoVo and OR-LoVo cells proliferation, invasion, and migration ability. Our results indicated that combined treatment of oxaliplatin with PD dramatically reduced the cellular proliferation in both LoVo and OR-LoVo cells. Furthermore, treatment with PD dose-dependently decreased LATS2/YAP1 hippo signaling and survival marker p-AKT expression, as well as increased cyclin-dependent kinase inhibitor proteins such as p21 and p27 expression. Importantly, PD activates and promotes YAP1 degradation through the ubiquitination and proteasome pathway. The nuclear transactivation of YAP was significantly reduced under PD treatment, leading to transcriptional inhibition of the downstream genes regulating cell proliferation, pro-survival, and metastasis. In conclusion, our results showed that PD is suitable as a promising agent for overcoming oxaliplatin-resistant colorectal cancer.

Unconditional and Robust Quantum Metrological Advantage beyond N00N States.

Quantum metrology employs quantum resources to enhance the measurement sensitivity beyond that can be achieved classically. While multiphoton entangled N00N states can in principle beat the shot-noise limit and reach the Heisenberg limit, high N00N states are difficult to prepare and fragile to photon loss which hinders them from reaching unconditional quantum metrological advantages. Here, we combine the idea of unconventional nonlinear interferometers and stimulated emission of squeezed light, previously developed for the photonic quantum computer Jiuzhang, to propose and realize a new scheme that achieves a scalable, unconditional, and robust quantum metrological advantage. We observe a 5.8(1)-fold enhancement above the shot-noise limit in the Fisher information extracted per photon, without discounting for photon loss and imperfections, which outperforms ideal 5-N00N states. The Heisenberg-limited scaling, the robustness to external photon loss, and the ease-of-use of our method make it applicable in practical quantum metrology at a low photon flux regime.