Exploring the Nonenzymatic Origin of Duclauxin-like Natural Products.

Chemical-biological efforts to increase the diversity of duclauxin (1)-like molecules for medicinal chemistry purposes unveiled the reactivity of duclauxin (1) toward amines and alcohols. To expand the compound class, a semisynthetic strategy conjugating amines to duclauxin (1) was employed. Insights gained from this approach led to the hypothesis that certain duclauxin-like "natural products" such as talaromycesone B (2), bacillisporin G (3), xenoclauxin (4), bacillisporins F (5/6), bacillisporins J (8/9), bacillisporins I (12/13), and verruculosin A (38) may be isolation artifacts rather than enzymatic products. Further experimentation, involving adsorption of 1 onto silica gel, resulted in the production of 2-6. To gain insights into the conditions that generate such molecules, one-step reactions under mild conditions were set. Outcomes from both experiments confirmed that duclauxin-like molecules are generated via nonenzymatic reactions. This article presents analytical evidence, indicating that these molecules originate from 1, with the epimeric mixture of bacillisporins J (8 and 9) acting as the primary intermediate.

Prevalence of pathogenic or likely pathogenic germline variants in cancer predisposition genes among selected patients with lung adenocarcinoma: The GERMLUNG study.

INTRODUCTION: Pathogenic or likely pathogenic germline variants (PGVs) in cancer predisposition genes may play a role in lung cancer (LC) susceptibility. However, determining an eligible population for genetic testing remains uncertain. This study aimed to assess the prevalence of PGVs in a selected cohort of individuals with lung adenocarcinoma. METHODS: A cross-sectional cohort study was conducted to assess the PGVs rate in lung adenocarcinoma patients with a family history of LC, young-onset presentation, history of never/light smoking, or actionable genomic alterations (AGAs). Sequencing was performed using Sophia Hereditary Cancer Solution panel F, including 144 cancer predisposition genes. Variants classified as pathogenic or likely pathogenic were included for further analysis. RESULTS: Of 201 patients, 43 (21.4 %) exhibited PGVs, among which 64.5 % were DNA damage repair genes, and 86.1 % were clinically actionable. The main PGVs were in ATM (9.3 %), TP53 (6.9 %), BRCA2 (6.9 %), and CHEK2 (6.9 %) genes. PGVs were associated with male sex (adjusted odds ratio [aOR] 2.46, 95 % CI 1.15-5.32, p = 0.021), along with a trend toward association with AGAs (aOR 6.04, 95 % CI 0.77-49.74, p = 0.094). CONCLUSIONS: In this study, a high PGVs prevalence was identified based on our selection criteria, which represents an effective strategy to identify candidates for germline genomic testing, potential screening strategies in close relatives, and personalized therapeutic modalities. Our results warrant further exploration in other populations to confirm them.

Open-source code maps traumas for targeting interventions: Applying the model to compare penetrating traumas with "Stop the Bleed" training locations.

BACKGROUND: To improve equitable access to geospatial analysis, a free open-source R package, called Rosymap, was created to map trauma incident locations. METHODS: To demonstrate the R package, penetrating trauma events for all patients who received care at a level one trauma center, and the locations of all "Stop the Bleed" training locations between 2019 and 2022 were geospatially analyzed. RESULTS: The level one trauma center treated 1531 patients for penetrating traumas between 2019 and 2022. Using Rosymap, a map was produced showing the poor overlap in distribution between penetrating traumas and "Stop the Bleed" training locations. CONCLUSION: Rosymap, a free open-source GIS R package, visualized that the majority of "Stop the Bleed" training locations were not performed within clusters of penetrating traumas serviced by our level one trauma center. These results suggest that trauma providers and public health advocates should consider geospatial analysis when planning interventions and when attempting to choose locations equitably and accurately. To facilitate and promote the implementation of geospatial analysis, Rosymap is available as open-source code.

Impact of KRASG12D subtype and concurrent pathogenic mutations on advanced non-small cell lung cancer outcomes / Impacto del subtipo KRASG12D y mutaciones patogénicas concurrentes en los resultados del cáncer de pulmón de células no pequeñas avanzado

Purpose: Mutations in the Kirsten rat sarcoma viral (KRAS) oncogene constitute a significant driver of lung adenocarcinoma, present in 10–40% of patients, which exhibit heterogeneous clinical outcomes, mainly driven by concurrent genetic alterations. However, characterization of KRAS mutational subtypes and their impact on clinical outcomes in Latin America is limited. Methods: A cohort study was conducted at the National Cancer Institute (INCan) of Mexico. Individuals with advance-staged of adenocarcinoma and KRAS mutations, detected by next-generation sequencing, having undergone at least one line of therapy were included for analysis. Clinical and pathological characteristics were retrieved from institutional database from June 2014 to March 2023. Results: KRAS was identified in fifty-four (15.6%) of 346 patients, among which 50 cases were included for analysis. KRASG12D (n = 16, 32%) and KRASG12C (n = 16, 32%) represented the most prevalent subtypes. KRASG12D mutations were associated with female (p = 0.018), never smokers (p = 0.108), and concurrences with EGFR (25.0% vs. 17.6%, p = 0.124) and CDKN2A (18.8% vs. 14.7%, p = 0.157). KRASG12D patients showed a better ORR (66.6% vs. 30.0%; OR 4.66, 95% CI 1.23–17.60, p = 0.023) and on multivariate analysis was significantly associated with better PFS (HR 0.36, 95% CI 0.16–0.80; p = 0.012) and OS (HR 0.24, 95% CI 0.08–0.70; p = 0.009). Conclusions: To our knowledge, this study represents the first effort to comprehensively characterize the molecular heterogeneity of KRAS-mutant NSCLC in Latin American patients. Our data reinforce the current view that KRAS-mutated NSCLC is not a single oncogene-driven disease and emphasizes the prognostic impact of diverse molecular profiles in this genomically defined subset of NSCLC. Further validation is warranted in larger multicenter Latin American cohorts to confirm our findings.(AU)

Stereoelectronic interactions are too weak to explain the molecular conformation in solid state of cis-2-tert-butyl-5-(tert-butylsulfonyl)-1,3-dioxane.

cis-2-tert-Butyl-5-(tert-butylsulfonyl)-1,3-dioxane (cis-1) exhibits a high degree of eclipsing in the H-C5-S-C segment in the solid state, the origin of which remains unexplained. The eclipsed conformation that corresponds to an energetic minimum in the solid state practically corresponds to a rotational transition state in solution, which allows an approach to understand transitions states. The difference in the enthalpy of sublimation ΔsubH between cis-1 and the more stable trans-1 is 8.40 kcal mol-1, lets to consider that the intermolecular interactions in the crystalline structure must be responsible for the conformational effect observed in the solid state. The study of the experimental electron density of cis-1 in solid state allowed to establish that CH⋯OS intermolecular interaction is the main contribution to the observed eclipsing. The charge density analysis was also performed using the quantum theory of atoms in molecules to evaluate the nature and relevance of the intermolecular interactions in the crystal structure.

Well-defined Cu(I) complexes based on [N,P]-pyrrole ligands catalyzed a highly endoselective 1,3-dipolar cycloaddition.

We herein report the synthesis and catalytic application of a new family of dinuclear Cu(I) complexes based on [N,P]-pyrrole ligands. The Cu(I) complexes (4a-d) were obtained in good yields and their catalytic properties were evaluated in the1,3-dipolar cycloaddition of azomethine ylides and electron-deficient alkenes. The air-stable complexes 4a-d exhibited high endo-diasteroselectivity to obtain substituted pyrrolidines, and the catalytic system showed excellent reactivity and wide substitution tolerance.

Impact of KRASG12D subtype and concurrent pathogenic mutations on advanced non-small cell lung cancer outcomes.

PURPOSE: Mutations in the Kirsten rat sarcoma viral (KRAS) oncogene constitute a significant driver of lung adenocarcinoma, present in 10-40% of patients, which exhibit heterogeneous clinical outcomes, mainly driven by concurrent genetic alterations. However, characterization of KRAS mutational subtypes and their impact on clinical outcomes in Latin America is limited. METHODS: A cohort study was conducted at the National Cancer Institute (INCan) of Mexico. Individuals with advance-staged of adenocarcinoma and KRAS mutations, detected by next-generation sequencing, having undergone at least one line of therapy were included for analysis. Clinical and pathological characteristics were retrieved from institutional database from June 2014 to March 2023. RESULTS: KRAS was identified in fifty-four (15.6%) of 346 patients, among which 50 cases were included for analysis. KRASG12D (n = 16, 32%) and KRASG12C (n = 16, 32%) represented the most prevalent subtypes. KRASG12D mutations were associated with female (p = 0.018), never smokers (p = 0.108), and concurrences with EGFR (25.0% vs. 17.6%, p = 0.124) and CDKN2A (18.8% vs. 14.7%, p = 0.157). KRASG12D patients showed a better ORR (66.6% vs. 30.0%; OR 4.66, 95% CI 1.23-17.60, p = 0.023) and on multivariate analysis was significantly associated with better PFS (HR 0.36, 95% CI 0.16-0.80; p = 0.012) and OS (HR 0.24, 95% CI 0.08-0.70; p = 0.009). CONCLUSIONS: To our knowledge, this study represents the first effort to comprehensively characterize the molecular heterogeneity of KRAS-mutant NSCLC in Latin American patients. Our data reinforce the current view that KRAS-mutated NSCLC is not a single oncogene-driven disease and emphasizes the prognostic impact of diverse molecular profiles in this genomically defined subset of NSCLC. Further validation is warranted in larger multicenter Latin American cohorts to confirm our findings.

Oxy- and Chloroarylation Pathways in Gold-Mediated Cyclization of 2-Aminoaryl-3-arylpropargyl-benzenesulfonamides.

A one-pot diazotization/gold-mediated cyclization of 2-aminoaryl-3-arylpropargyl-benzenesulfonamides is described. After diazotization, Me2 SAuCl triggers an oxy- and/or chloroarylation of the alkyne moiety, resulting in the formation of 3-acylindoles and/or Z-3-(chloromethylene)indolines. Density Functional Theory (DFT) calculations show the significant energetic preference of both processes over an insertion pathway. Notably, a Z-3-(chloromethylene)indoline crystallized with [Cl-Au-Cl],- exhibiting Au⋅⋅⋅H-C short contacts.

A Novel Combination of Sotorasib and Metformin Enhances Cytotoxicity and Apoptosis in KRAS-Mutated Non-Small Cell Lung Cancer Cell Lines through MAPK and P70S6K Inhibition.

Novel inhibitors of KRAS with G12C mutation (sotorasib) have demonstrated short-lasting responses due to resistance mediated by the AKT-mTOR-P70S6K pathway. In this context, metformin is a promising candidate to break this resistance by inhibiting mTOR and P70S6K. Therefore, this project aimed to explore the effects of the combination of sotorasib and metformin on cytotoxicity, apoptosis, and the activity of the MAPK and mTOR pathways. We created dose-effect curves to determine the IC50 concentration of sotorasib, and IC10 of metformin in three lung cancer cell lines; A549 (KRAS G12S), H522 (wild-type KRAS), and H23 (KRAS G12C). Cellular cytotoxicity was evaluated by an MTT assay, apoptosis induction through flow cytometry, and MAPK and mTOR pathways were assessed by Western blot. Our results showed a sensitizing effect of metformin on sotorasib effect in cells with KRAS mutations and a slight sensitizing effect in cells without K-RAS mutations. Furthermore, we observed a synergic effect on cytotoxicity and apoptosis induction, as well as a notable inhibition of the MAPK and AKT-mTOR pathways after treatment with the combination, predominantly in KRAS-mutated cells (H23 and A549). The combination of metformin with sotorasib synergistically enhanced cytotoxicity and apoptosis induction in lung cancer cells, regardless of KRAS mutational status.

Synthesis of (µ2,η3-allyl-η5-oxapentadienyl)diiron pentacarbonyl complexes, an unusual reaction product from η4-(vinylketene)Fe(CO)3 complexes: structure and electron density distribution analysis.

The synthesis of a series of ferrocenylvinylketenes as stable η4-[Fe(CO)3] complexes (3a-f) was successfully accomplished through the reaction of η2-[Fe(CO)4] complexes under mild carbonylation conditions. The reactivity of 3a-f under thermal conditions afforded the unexpected formation of a novel family of (µ2,η3-allyl-η5-oxapentadienyl)diiron pentacarbonyl complexes 5a-f proposed to be formed by a sequence metathesis-haptotropic rearrangement between the starting η4-vinylketene iron(0) complex 3 and a η4-vinylcarbene iron(0) complex trapped in situ after a reversible carbonylation process favored by the thermal conditions. An electron density distribution analysis (EDD) of 5e using high-resolution X-ray diffraction data in combination with the DFT framework was performed to understand the electronic communication between the two iron fragments.

Weighted Blankets for Pain and Anxiety Relief in Acutely Injured Trauma Patients.

To determine the impact of a weighted blanket on acute pain and anxiety in trauma patients, a preliminary prospective/retrospective study at a level-one trauma center (n = 24 patients) was conducted. In this study, 12 patients using weighted blankets for five consecutive days were compared to a matched retrospective cohort of 12 patients not using a blanket. The change in morphine milligram equivalents (MME) and alprazolam milligram equivalents (AME) over five days were compared. There was a significant difference of MME per day between the intervention group (mean MME change = -22.9) and matched controls (mean MME change = 6.2; p = 0.0072) by blanket use. Total MMEs in the intervention group decreased by 275.5 and in the control group increased by 75 between day 1 and day 5. There was no significant difference in AME change between groups (p = 0.3227). The majority of patients who took a post-intervention questionnaire reported less pain and less anxiety with blanket use compared to those without blanket use (78% and 56% of patients, respectively). To summarize, trauma patients in acute pain had less opioid use and reported less pain and anxiety when using a weighted blanket for five consecutive days compared to a control group who did not use a blanket.

Activities Performed by ASCO-Sponsored Oncology Student Interest Groups in Latin America: Assessing Members' Preferences and Leaders' Challenges.

PURPOSE: In response to the worldwide shortage of oncologists, ASCO established Oncology Student Interest Groups (OSIGs) to increase oncology exposure at medical schools. However, there is limited guidance on the activities they should undergo. The main purposes of this study were (1) to assess the preferences and perceptions of OSIG members about their group events and (2) to describe the difficulties faced by leaders to carry out OSIGs' tasks. METHODS: In this multicenter, cross-sectional study, group members and leaders from five active Latin American OSIGs were invited to answer anonymous web-based surveys exploring members' attitudes toward group activities and leaders' challenges when carrying them out. Data collection was conducted from March to June 2021. RESULTS: Responses from 142 medical students and four OSIGs leaders were analyzed. In total, 83% of student members considered that lectures with an oncology-related expert was very useful for increasing their overall interest in oncology. For increasing interest in cancer research, 87% deemed that participating in oncology research projects was very useful. Shadowing oncology professionals was very useful for at least 70% of members to increase their oncology knowledge and their interest in following an oncology-related career. Moreover, leaders' main challenges were having a high academic load, little response from members, lack of interesting ideas and protected time for OSIGs' events, and limited support from their school. CONCLUSION: OSIGs' leaders, medical schools, and international oncology organizations should work together to design activities that increase medical students' exposure to oncology-related professionals and encourage their participation in international oncological events. These schools and organizations should actively support OSIG leaders when facing difficulties to prevent members' disengagement and groups' discontinuation.

Formation of the quasi-planar B56 boron cluster: topological path from B12 and disk aromaticity.

Formation and stability of the B56 boron cluster were investigated using a topological approach and the disk aromaticity model. An extensive global energy minimum search for the B56 system which was carried out by means of the Mexican Enhanced Genetic Algorithm (MEGA) in conjunction with density functional theory computations, confirms a quasi-planar structure as its energetically most stable isomer. Such a structural motif is derived by applying a topological leapfrog operation to a B12 form. Its high thermodynamic stability can be explained by the disk aromaticity model in which the delocalization of its π orbitals can be assigned to the levels of a particle in a circular box with the [(1σ)2 (1π)4 (1δ)4 (1φ)4 (2σ)2 (1γ)4 (2π)4 (2δ)4 (1η)4 (2φ)4 (1θ)2] electronic configuration. This π delocalization is confirmed by other delocalization indices. While the B56 has a similar electron delocalization to that of the quasi-planar B50, they have opposite magnetic ring current properties because of the symmetry selection rules of their HOMO-LUMO electronic transitions. The π delocalization in the boron clusters is larger at long distances as compared to carbon clusters at similar sizes, but such a trend is reversed at shorter distances.

Benzene and Borazine, so Different, yet so Similar: Insight from Experimental Charge Density Analysis.

Although benzene and borazine are isoelectronic and isostructural, they have very different electronic structures, mainly due to the polar nature of the B-N bond. Herein, we present an experimental study of the charge density distribution obtained from the multipole model formalism and Hirshfeld atom refinement (HAR) based on high-resolution X-ray diffraction data of borazine B3N3H6 (1) and B,B',B″-trichloroborazine (2) crystals. These data are compared to those obtained from HAR for benzene (4) and 1,3,5-trichlorobenzene (5) and further compared with values obtained from density functional theory calculations in the gas phase, where N,N',N″-trichloroborazine (3) was also included. The results confirm that, unlike benzene, borazines are only weakly aromatic with an island-like electronic delocalization within the B3N3 ring involving only the nitrogen atoms. Furthermore, delocalization indices and interacting quantum atom energy for bonded and non-bonded atoms were found to be highly suitable indicators capable of describing the origin of the discrepancies observed when the degree of aromaticity in 2 and 3 is evaluated using common aromaticity indices. Additionally, analysis of intermolecular interactions in the crystals brings further evidence of a weakly aromatic character of the borazines as it reveals surprising similarities between the crystal packing of borazine and benzene and also between B,B',B″-trichloroborazine and 1,3,5-trichlorobenzene.

Iodine-promoted insertion of the oxygen atom from water in η4-vinylketene[Fe(CO)3] complexes.

Iodine promotes the in situ formation of iron(II) species from η4-vinylketene[Fe(CO)3] (3a-h) as a key intermediate for the synthesis of 2(5H)-furanones (4a-h) by a sequential water-insertion/carbon-oxygen coupling under mild reaction conditions. Compounds 4a-h were obtained in good to excellent yields. A possible reaction pathway was also proposed by DFT calculations. This methodology can be extended to the synthesis of (5H)-pyrrol-2-ones using anilines, with moderate yields and a few limitations.

Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial-Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells.

The combination of metformin and TKIs for non-small cell lung cancer has been proposed as a strategy to overcome resistance of neoplastic cells induced by several molecular mechanisms. This study sought to investigate the effects of a second generation TKI afatinib, metformin, or their combination on three adenocarcinoma lung cancer cell lines with different EGFRmutation status. A549, H1975, and HCC827 cell lines were treated with afatinib, metformin, and their combination for 72 h. Afterwards, several parameters were assessed including cytotoxicity, interactions, apoptosis, and EGFR protein levels at the cell membrane and several glycolytic, oxidative phosphorylation (OXPHOS), and EMT expression markers. All cell lines showed additive to synergic interactions for the induction of cytotoxicity caused by the tested combination, as well as an improved pro-apoptotic effect. This effect was accompanied by downregulation of glycolytic, EMT markers, a significant decrease in glucose uptake, extracellular lactate, and a tendency towards increased OXPHOS subunits expression. Interestingly, we observed a better response to the combined therapy in lung cancer cell lines A549 and H1975, which normally have low affinity for TKI treatment. Findings from this study suggest a sensitization to afatinib therapy by metformin in TKI-resistant lung cancer cells, as well as a reduction in cellular glycolytic phenotype.

Delayed traumatic rupture of ovarian endometrioma on re-exploration after blunt abdominal trauma.

Traumatic rupture of an ovarian endometrioma is extremely rare injury. We describe a case of a 63-year-old female presenting after a motor vehicle crash (MVC) with complex abdominal injuries requiring exploratory laparotomy that was complicated by delayed presentation of an ovarian endometrioma rupture on second look laparotomy. During the repeat exploration of the abdomen, multiple regions of small bowel and the pelvic floor were noted to be covered with a brown-colored material which was concerning for fecal matter from a missed enterotomy. The patient was kept open for an additional 24 h providing time for occult injuries to reveal themselves and for proper mechanical preparation of the rectum to perform rigid sigmoidoscopy, essential to definitively rule out a missed injury in this rare situation.

Use of Low-Molecular-Weight Heparin and Peak anti-Xa Monitoring In Severe SARS-CoV-2 Disease: A Brief Report.

In 2019, a novel coronavirus was identified in Wuhan, China. This strain was classified as a pandemic in early 2020 by the World Health Organization (WHO), rapidly reaching millions of cases worldwide and overwhelming intensive care units. One distinct feature identified in severe SARS-CoV-2 is abnormal and complex coagulation and hematologic abnormalities, including significantly elevated D-dimer and fibrin/fibrinogen values possibly increasing morbidity and mortality in this patient population. Aggressive anticoagulation therapy with appropriate peak anti-Xa level monitoring has produce satisfactory results at our institution. Our intent is to present a case series of our strategy to highlight the benefits of this approach.

Effect of the nO → π*C═O Interaction on the Conformational Preference of 1,3-Diketones: A Case Study of Riolozatrione Derivatives.

The cyclopropane ring-opening reaction of riolozatrione, a natural product obtained from Jatropha dioica, afforded a 2,2-disubstituted 1,3-cyclohexandione displaying an alkyl methyl ether group at position 5. The conformational analysis of this product showed a high preference for the trans-diaxial conformation in both solution and solid state. Such conformation was possible from the noncovalent intramolecular nX → π*C═O interactions (X = an element having an unshared electron pair), allowing the determination of the interaction energies. Since the nX → π*C═O interactions can be regarded as additive, the energy values ranged from 4.52 to 6.51 kcal mol-1 for each carbonyl group with a strong dependency on the interatomic distances. The rigorous analysis of the electron density in the topological theory of atoms in molecules framework clearly shows that the origin of O-C═O interactions are through the nO → π*C═O electron transfer mechanism. Such interactions are slightly weaker than a canonical hydrogen bond but seemingly stronger than a van der Waals interaction. This interaction must be considered as a stereoelectronic effect due the electronic transfer between the interacting groups, which are limited by their relative stereochemistry and can be represented by a bond-no bond interaction, causing the pyramidalization of the carbonyl, which is the charge acceptor group.