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An examination is done on femtosecond transient absorption spectra of molecules in solution change when an ultrafast reaction creates a new product state, and coherent optical processes complicate the spectra during the pump pulse. In conclusion, the spectra of all species are obtained and decomposed.

Modeling and simulation of small molecules such as drugs and biological cofactors have been both a major focus of computational chemistry for decades and a growing need among computational biophysicists who seek to investigate the interaction of different types of ligands with biomolecules. Of particular interest in this regard are quantum mechanical (QM) calculations that are used to more accurately describe such small molecules, which can be of heterogeneous structures and chemistry, either in purely QM calculations or in hybrid QM/molecular mechanics (MM) simulations. QM programs are also used to develop MM force field parameters for small molecules to be used along with established force fields for biomolecules in classical simulations. With this growing need in mind, here we report a set of software tools developed and closely integrated within the broadly used molecular visualization/analysis program, VMD, that allow the user to construct, modify, and parametrize small molecules and prepare them for QM, hybrid QM/MM, or classical simulations. The tools also provide interactive analysis and visualization capabilities in an easy-to-use and integrated environment. In this paper, we briefly report on these tools and their major features and capabilities, along with examples of how they can facilitate molecular research in computational biophysics that might be otherwise prohibitively complex.

Purpose: KRAS is the most mutated proto-oncogene that has been identified in cancer, and treatment of patients with KRAS mutations remains an arduous challenge. Recently, KRAS G12C mutation has attracted special interest because it is now considered potentially druggable with recently developed covalent small-molecule KRAS G12C inhibitors. Nevertheless, to date, there have been no large-scale analyses of liquid biopsy that include testing for KRAS G12C . Here, we performed a comprehensive analysis of KRAS G12C mutations in multiple cancer types, as detected by circulating tumor DNA., Methods: We conducted a 5-year retrospective review of KRAS G12C mutations in patients with cancer who had undergone Guardant360 testing between July 1, 2014, and June 30, 2019; our study included treatment-naive and previously treated patients with metastatic solid tumors., Results: KRAS G12C mutations were identified in 2,985 of 80,911 patients (3.7%), across > 40 tumor types. KRAS G12C mutations were detected most frequently in patients with nonsquamous non-small-cell lung cancer (NSCLC; 7.5%), NSCLC of all subtypes (6.9%), cancer of unknown primary (4.1%), colorectal cancer (3.5%), squamous NSCLC (2.0%), pulmonary neuroendocrine tumors (1.9%), and pancreatic ductal adenocarcinoma (1.2%) and cholangiocarcinoma (1.2%). KRAS G12C mutations were predominantly clonal (clonality > 0.9%) in patients with lung adenocarcinoma, non-NSCLC, cancer of unknown primary, NSCLC, and pancreatic ductal adenocarcinoma, and patients with colorectal cancer and breast cancer had bimodal distribution of clonal and subclonal KRAS G12C mutations., Conclusion: Our study demonstrates the feasibility of using circulating tumor DNA to identify KRAS G12C mutations across solid tumors; the highest detection rate was in lung cancer, as previously reported in the literature.

Fatty acid beta-oxidation is a key process in mammalian lipid catabolism. Disturbance of this process results in severe clinical symptoms, including dysfunction of the liver, a major beta-oxidizing tissue. For a thorough understanding of this process, a comprehensive analysis of involved fatty acid and acyl-carnitine intermediates is desired, but capable methods are lacking. Here, we introduce oxaalkyne and alkyne fatty acids as novel tracers to study the beta-oxidation of long- and medium-chain fatty acids in liver lysates and primary hepatocytes. Combining these new tracer tools with highly sensitive chromatography and mass spectrometry analyses, this study confirms differences in metabolic handling of fatty acids of different chain length. Unlike longer chains, we found that medium-chain fatty acids that were activated inside or outside of mitochondria by different acyl-CoA synthetases could enter mitochondria in the form of free fatty acids or as carnitine esters. Upon mitochondrial beta-oxidation, shortened acyl-carnitine metabolites were then produced and released from mitochondria. In addition, we show that hepatocytes ultimately also secreted these shortened acyl chains into their surroundings. Furthermore, when mitochondrial beta-oxidation was hindered, we show that peroxisomal beta-oxidation likely acts as a salvage pathway, thereby maintaining the levels of shortened fatty acid secretion. Taken together, we conclude that this new method based on oxaalkyne and alkyne fatty acids allows for metabolic tracing of the beta-oxidation pathway in tissue lysate and in living cells with unique coverage of metabolic intermediates and at unprecedented detail., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer of unknown primary (CUP) is a metastatic disease with unidentifiable primary tumor. Somatic alterations can be assessed noninvasively via liquid biopsies interrogating cell-free DNA (cfDNA)., Methods: We evaluated 1,931 patients with CUP with a cfDNA next-generation sequencing panel (73-74 genes)., Results: Overall, 1,739 patients (90%) had ≥ 1 cfDNA alteration. We then explored alteration actionability (per the levels of evidence from the OncoKB database); 825 patients (47.4% of 1,739) had level 1, level 2, or resistance/R1 alterations. Among 40 clinically annotated patients with CUP who had cfDNA evaluated, higher degrees of matching treatment to alterations (Matching Score > 50% v ≤ 50%) was the only variable predicting improved outcome: longer median progression-free survival (10.4 v 2.5 months; P = .002), overall survival (13.4 v 5.7 months; P = .07, trend), and higher clinical benefit rate (stable disease ≥ 6 months/partial response/complete response; 83% v 25%; P = .003)., Conclusion: In summary, cfDNA frequently reveals strong level-of-evidence actionable alterations in CUP, and high degrees of matching to therapy correlates with better outcomes., Competing Interests: Razelle Kurzrock Leadership: CureMatch, CureMetrix Stock and Other Ownership Interests: CureMatch, IDbyDNA Honoraria: Roche, EUSA Pharma, NeoGenomics Laboratories, Biocom, NeoMed, Advanced Therapeutics, LEK, AACR, Chugai Pharma USA, Wiley, Merck, Pfizer, Meyer Consulting, Foundation Medicine, Turning Point Therapeutics, Bicara Therapeutics Consulting or Advisory Role: Actuate Therapeutics, XBiotech, NeoMed, Gaido, Soluventis, Pfizer, Merck, Turning Point Therapeutics, TD2/Volastra, Bicara Therapeutics Speakers' Bureau: Roche Research Funding: Guardant Health, Sequenom, Merck Serono, Genentech, Pfizer, Foundation Medicine, Incyte, Konica Minolta, Grifols, OmniSeq, Debiopharm Group, Boehringer Ingelheim, Top Alliance BioScience, Takeda, MedImmune Travel, Accommodations, Expenses: EUSA Pharma, NeoGenomics Laboratories, Biocom, NeoMed, Advanced Therapeutics, LEK, AACR, Chugai Pharma USA, Wiley No other potential conflicts of interest were reported. Razelle Kurzrock Leadership: CureMatch, CureMetrix Stock and Other Ownership Interests: CureMatch, IDbyDNA Honoraria: Roche, EUSA Pharma, NeoGenomics Laboratories, Biocom, NeoMed, Advanced Therapeutics, LEK, AACR, Chugai Pharma USA, Wiley, Merck, Pfizer, Meyer Consulting, Foundation Medicine, Turning Point Therapeutics, Bicara Therapeutics Consulting or Advisory Role: Actuate Therapeutics, XBiotech, NeoMed, Gaido, Soluventis, Pfizer, Merck, Turning Point Therapeutics, TD2/Volastra, Bicara Therapeutics Speakers' Bureau: Roche Research Funding: Guardant Health, Sequenom, Merck Serono, Genentech, Pfizer, Foundation Medicine, Incyte, Konica Minolta, Grifols, OmniSeq, Debiopharm Group, Boehringer Ingelheim, Top Alliance BioScience, Takeda, MedImmune Travel, Accommodations, Expenses: EUSA Pharma, NeoGenomics Laboratories, Biocom, NeoMed, Advanced Therapeutics, LEK, AACR, Chugai Pharma USA, Wiley No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC) 1-3 . Targeted therapies are approved for patients with 'classical' mutations and a small number of other mutations 4-6 . However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown 1,3,7-10 . Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure-function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure-function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations., (© 2021. The Author(s).)