Discovery of a Novel and Potent LCK Inhibitor for Leukemia Treatment via Deep Learning and Molecular Docking.

The lymphocyte-specific protein tyrosine kinase (LCK) plays a crucial role in both T-cell development and activation. Dysregulation of LCK signaling has been demonstrated to drive the oncogenesis of T-cell acute lymphoblastic leukemia (T-ALL), thus providing a therapeutic target for leukemia treatment. In this study, we introduced a sophisticated virtual screening strategy combined with biological evaluations to discover potent LCK inhibitors. Our initial approach involved utilizing the PLANET algorithm to assess and contrast various scoring methodologies suitable for LCK inhibitor screening. After effectively evaluating PLANET, we progressed to devise a virtual screening workflow that synergistically combines the strengths of PLANET with the capabilities of Schrödinger's suite. This integrative strategy led to the efficient identification of four potential LCK inhibitors. Among them, compound 1232030-35-1 stood out as the most promising candidate with an IC50 of 0.43 nM. Further in vitro bioassays revealed that 1232030-35-1 exhibited robust antiproliferative effects on T-ALL cells, which was attributed to its ability to suppress the phosphorylations of key molecules in the LCK signaling pathway. More importantly, 1232030-35-1 treatment demonstrated profound in vivo antileukemia efficacy in a human T-ALL xenograft model. In addition, complementary molecular dynamics simulations provided deeper insight into the binding kinetics between 1232030-35-1 and LCK, highlighting the formation of a hydrogen bond with Met319. Collectively, our study established a robust and effective screening strategy that integrates AI-driven and conventional methodologies for the identification of LCK inhibitors, positioning 1232030-35-1 as a highly promising and novel drug-like candidate for potential applications in treating T-ALL.

Severe community-acquired pneumonia caused by Leptospira interrogans: A case report and review of literature.

BACKGROUND: Leptospira is an uncommon pathogen for adult severe community-acquired pneumonia and its nonspecific manifestations and limited diagnostic tests make it difficult to identify. Although conventional penicillin remains efficacious to treat leptospirosis, failure in early diagnosis and treatment can lead to progression into a deadly syndrome with multiple organ dysfunction. Next generation sequencing is of great value to understand cases with infection of unknown cause, which could help in the diagnosis of uncertain Leptospira infection. CASE SUMMARY: We recently managed a patient with fever, cough and dyspnea on admission that progressed into persistent adult respiratory distress syndrome, hemoptysis and hematuria after admission. In this case, the rare Leptospira infection was clouded by the positive influenza tests at admission, delaying early Leptospira-targeted antibiotics administration. Next generation sequencing, a novel molecular diagnostic tool, provided a key hint to uncover the crucial pathogen, Leptospira interrogans, further supported by the possible occupational exposure history. Subsequent conventional penicillin and mechanical respiratory support were administrated to cure the patient successfully without any sequela. CONCLUSION: Clinicians must pay attention to possible exposure history and keep uncommon Leptospira in mind when managing pneumonia with unknown causes.

A new small-angle X-ray scattering model for polymer spherulites with a limited lateral size of the lamellar crystals.

As is well known, polymers commonly form lamellar crystals, and these assemble further into lamellar stacks and spherulites during quiescent crystallization. Fifty years ago, Vonk and Kortleve constructed the classical small-angle X-ray scattering theory (SAXS) for a lamellar system, in which it was assumed that the lamellar stack had an infinite lateral size [Vonk & Kortleve (1967 ▸), Kolloid Z. Z. Polym. 220, 19-24]. Under this assumption, only crystal planes satisfying the Bragg condition can form strong scattering, and the scattering from the lamellar stack arises from the difference between the scattering intensities in the amorphous and crystalline layers, induced by the incident X-ray beam. This assumption is now deemed unreasonable. In a real polymer spherulite, the lamellar crystal commonly has dimensions of only a few hundred nanometres. At such a limited lateral size, lamellar stacks in a broad orientation have similar scattering, so interference between these lamellar stacks must be considered. Scattering from lamellar stacks parallel to the incident X-ray beam also needs to be considered when total reflection occurs. In this study, various scattering contributions from lamellar stacks in a spherulite are determined. It is found that, for a limited lateral size, the scattering induced by the incident X-ray beam is not the main origin of SAXS. It forms double peaks, which are not observed in real scattering because of destructive interference between the lamellar stacks. The scattering induced by the evanescent wave is the main origin. It can form a similar interference pattern to that observed in a real SAXS measurement: a Guinier region in the small-q range, a signal region in the intermediate-q range and a Porod region in the high-q range. It is estimated that, to avoid destructive interference, the lateral size needs to be greater than 11 µm, which cannot be satisfied in a real lamellar system. Therefore, SAXS in a real polymer system arises largely from the scattering induced by the evanescent wave. Evidence for the existence of the evanescent wave was identified in the scattering of isotactic polypropyl-ene. This study corrects a long-term misunderstanding of SAXS in a polymer lamellar system.

Positron emission tomography/computed tomography in the diagnosis, staging, and prognostic evaluation of natural killer/T-cell lymphoma.

Natural killer/T-cell lymphoma (NKTL) is a rare subtype of non-Hodgkin's lymphoma that is associated with Epstein-Barr virus infection. The clinicopathological features of NKTL are unique among lymphomas. NKTL is an aggressive disease with a poor prognosis in the absence of effective treatment. Accurate diagnosis and staging are essential to ensure an appropriate treatment strategy and accurate prognosis of NKTL. 18F-Fluorodexoyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) is a valuable technique in the diagnosis, staging, and prognostic evaluation of various types of malignant tumors, including NKTL. PET/CT imaging studies of patients with NKTL have shown that NKTL is 18F-FDG-avid and that PET/CT is superior to conventional methods in detecting cutaneous and extracutaneous lesions. We herein review recent PET/CT studies that have provided considerable insight into the diagnosis, staging, prognostic evaluation, and treatment effectiveness in patients with NKTL.

Combinatorial study of the optimization of Y2O3:Bi,Eu red phosphors.

The present investigation aims at the synthesis of (Y2-xEuxBiy)O3 red phosphor materials using the combinatorial chemistry method. We developed square-type arrays consisting of 90 compositions to obtain the optimum composition of co-dopants in a Y2O3 host. The optimized composition was found to be (Y2-xEuxBiy)O3 (x = 0.16-0.18, y = 0.08-0.10). The screening of the compositions was investigated by analysis of the emission spectrum under 365 nm UV excitation arising from the energy transfer between Bi3+ and Eu3+ ions. The results of the photoluminescence excited by ultraviolet agree well with the conventional-scale synthesis results, indicating that the combinatorial screening method is fast, reliable, reproducible, and applicable to the study of powder materials with relatively quick calcinations at high synthesis temperatures.

Combinatorial study of cofluorescence of rare earth organic complexes doped in the poly(methyl methacrylate) matrix.

The luminescence enhancement effect of different kinds and contents of rare earth complexe (RE(DBM)3Phen, RE = Dy, La, Gd, Sm, Y; DBM = dibenzoylmethane; Phen = 1,10-phenanthroline) sensitized Eu(DBM)3Phen doped in poly(methyl methacrylate) (PMMA) matrix was investigated using the combinatorial method. The efficiency of the luminescence enhancement increases with a decrease in the weight percentage of the Eu(DBM)3Phen and an increase in the molecular weight of the PMMA in the systems. Among these sensitization ion complexes, La(DBM)3Phen shows the highest sensitization efficiency. At the optimal content of 5 wt % Eu(DBM)3Phen and 350,000 g/mol weight average molecular weight (Mw) of PMMA, the maximum sensitization efficiency of La(DBM)3Phen is approximately 20 times. We believe that the PMMA with high molecular weight enwraps the rare earth complexes and keeps the donors and acceptors close, which results in the effective intermolecular energy transfer and, consequently, the high sensitization efficiency.