Implementation of The Future of Drug Discovery: QuantumBased Machine Learning Simulation (QMLS)

The Research & Development (R&D) phase of drug development is a lengthy and costly process. To revolutionize this process, we introduce our new concept QMLS to shorten the whole R&D phase to three to six months and decrease the cost to merely fifty to eighty thousand USD. For Hit Generation, Machine Learning Molecule Generation (MLMG) generates possible hits according to the molecular structure of the target protein while the Quantum Simulation (QS) filters molecules from the primary essay based on the reaction and binding effectiveness with the target protein. Then, For Lead Optimization, the resultant molecules generated and filtered from MLMG and QS are compared, and molecules that appear as a result of both processes will be made into dozens of molecular variations through Machine Learning Molecule Variation (MLMV), while others will only be made into a few variations. Lastly, all optimized molecules would undergo multiple rounds of QS filtering with a high standard for reaction effectiveness and safety, creating a few dozen pre-clinical-trail-ready drugs. This paper is based on our first paper, where we pitched the concept of machine learning combined with quantum simulations. In this paper we will go over the detailed design and framework of QMLS, including MLMG, MLMV, and QS.Comment: 13 pages, 6 figure

A CsI hodoscope on CSHINE for Bremsstrahlung {\gamma}-rays in Heavy Ion Reactions

Bremsstrahlung $\gamma$ production in heavy ion reactions at Fermi energies carries important physical information including the nuclear symmetry energy at supra-saturation densities. In order to detect the high energy Bremsstrahlung $\gamma$ rays, a hodoscope consisting of 15 CsI(Tl) crystal read out by photo multiplier tubes has been built, tested and operated in experiment. The resolution, efficiency and linear response of the units to $\gamma$ rays have been studied using radioactive source and $({\rm p},\gamma)$ reactions. The inherent energy resolution of $1.6\%+2\%/E_{\gamma}^{1/2}$ is obtained. Reconstruction method has been established through Geant 4 simulations, reproducing the experimental results where comparison can be made. Using the reconstruction method developed, the whole efficiency of the hodoscope is about $2.6\times 10^{-4}$ against the $4\pi$ emissions at the target position, exhibiting insignificant dependence on the energy of incident $\gamma$ rays above 20 MeV. The hodoscope is operated in the experiment of $^{86}$Kr + $^{124}$Sn at 25 MeV/u, and a full $\gamma$ energy spectrum up to 80 MeV has been obtained.Comment: 9 pages, 19 figure

Whole exome sequencing identifies frequent somatic mutations in cell-cell adhesion genes in chinese patients with lung squamous cell carcinoma

Lung squamous cell carcinoma (SQCC) accounts for about 30% of all lung cancer cases. Understanding of mutational landscape for this subtype of lung cancer in Chinese patients is currently limited. We performed whole exome sequencing in samples from 100 patients with lung SQCCs to search for somatic mutations and the subsequent target capture sequencing in another 98 samples for validation. We identified 20 significantly mutated genes, including TP53, CDH10, NFE2L2 and PTEN. Pathways with frequently mutated genes included those of cell-cell adhesion/Wnt/Hippo in 76%, oxidative stress response in 21%, and phosphatidylinositol-3-OH kinase in 36% of the tested tumor samples. Mutations of Chromatin regulatory factor genes were identified at a lower frequency. In functional assays, we observed that knockdown of CDH10 promoted cell proliferation, soft-agar colony formation, cell migration and cell invasion, and overexpression of CDH10 inhibited cell proliferation. This mutational landscape of lung SQCC in Chinese patients improves our current understanding of lung carcinogenesis, early diagnosis and personalized therapy

Focal Adhesion Kinase (FAK) promotes cholangiocarcinoma development and progression via YAP activation

Background & aimsFocal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is upregulated in many tumor types and is a promising target for cancer therapy. Herein, we elucidated the functional role of FAK in intrahepatic cholangiocarcinoma (iCCA) development and progression.MethodsExpression levels and activation status of FAK were determined in human iCCA samples. The functional contribution of FAK to Akt/YAP murine iCCA initiation and progression was investigated using conditional Fak knockout mice and constitutive Cre or inducible Cre mice, respectively. The oncogenic potential of FAK was further examined via overexpression of FAK in mice. In vitro cell line studies and in vivo drug treatment were applied to address the therapeutic potential of targeting FAK for iCCA treatment.ResultsFAK was ubiquitously upregulated and activated in iCCA lesions. Ablation of FAK strongly delayed Akt/YAP-driven mouse iCCA initiation. FAK overexpression synergized with activated AKT to promote iCCA development and accelerated Akt/Jag1-driven cholangiocarcinogenesis. Mechanistically, FAK was required for YAP(Y357) phosphorylation, supporting the role of FAK as a central YAP regulator in iCCA. Significantly, ablation of FAK after Akt/YAP-dependent iCCA formation strongly suppressed tumor progression in mice. Furthermore, a remarkable iCCA growth reduction was achieved when a FAK inhibitor and palbociclib, a CDK4/6 inhibitor, were administered simultaneously in human iCCA cell lines and Akt/YAP mice.ConclusionsFAK activation contributes to the initiation and progression of iCCA by inducing the YAP proto-oncogene. Targeting FAK, either alone or in combination with anti-CDK4/6 inhibitors, may be an effective strategy for iCCA treatment.Lay summaryWe found that the protein FAK (focal adhesion kinase) is upregulated and activated in human and mouse intrahepatic cholangiocarcinoma samples. FAK promotes intrahepatic cholangiocarcinoma development, whereas deletion of FAK strongly suppresses its initiation and progression. Combined FAK and CDK4/6 inhibitor treatment had a strong anti-cancer effect in in vitro and in vivo models. This combination therapy might represent a valuable and novel treatment against human intrahepatic cholangiocarcinoma

New trapezoid-shaped Frisch-grid ionization chamber for low-energy particle measurements

A new trapezoid-shaped Frisch-grid ionization chamber (TFG-IC) has been built as a part of a $$\varDelta {E}-E$$ telescope system for the detection and identification of charged particles at energies down to a few MeV. To study the effect of the drift electric field uniformity, two types of sealed windows, namely a pair of SSA (split-strip aluminized mylar film) and a pair of DSA (double-sided aluminized mylar film) sealed windows have been investigated. The detector’s performances were studied using a standard $$^{241}$$Am source at different gas pressures, and the total energy-deposit resolution achieved is about 1.1%(FWHM). The $$\varDelta {E}-E$$ telescope, which was composed of TFG-IC and a DSSSD (double-sided silicon strip detector), has been tested using a three-component $$\alpha$$ source and the $$^{241}$$Am source under laboratory conditions. The results show that the energy resolution with the SSA sealed windows which provide uniform drift electric field has a smaller fluctuation than that with the DSA ones; the fluctuations are about 1% and 4% for the former and the latter, respectively. Simulations using the COMSOL software also confirmed the electric-field distortion at the edge of the detector with the DSA windows. A correlation curve between energy resolution and energy deposit of charged particles at various gas pressures and for two gas species is derived for TFG-IC with the SSA sealed windows using the measurement with the $$^{241}$$Am source. Incorporating the above results, we performed Monte Carlo simulations to evaluate the particle-identification capability of the telescope. The results show that the telescope can be extended to the identification of low-energy particles

Probing high-momentum component in nucleon momentum distribution by neutron-proton bremsstrahlung γ-rays in heavy ion reactions

The high momentum tail (HMT) of nucleons, as a signature of the short-range correlations in nuclei, has been investigated by the high-energy bremsstrahlung γ rays produced in 86Kr+124Sn at 25 MeV/nucleon. The energetic photons are measured by a CsI(Tl) hodoscope mounted on the spectrometer CSHINE. The energy spectrum ≥35 MeV can be reproduced by the Isospin- and Momentum-Dependent Boltzmann-Uehling-Uhlenbeck model calculations incorporating the photon production channel from np process in which the HMTs of nucleons is considered. A non-zero HMT ratio of about 15% is favored by the data. The effect of the capture channel np→dγ is demonstrated