Empowering natural product science with AI: leveraging multimodal data and knowledge graphs.

Artificial intelligence (AI) is accelerating how we conduct science, from folding proteins with AlphaFold and summarizing literature findings with large language models, to annotating genomes and prioritizing newly generated molecules for screening using specialized software. However, the application of AI to emulate human cognition in natural product research and its subsequent impact has so far been limited. One reason for this limited impact is that available natural product data is multimodal, unbalanced, unstandardized, and scattered across many data repositories. This makes natural product data challenging to use with existing deep learning architectures that consume fairly standardized, often non-relational, data. It also prevents models from learning overarching patterns in natural product science. In this Viewpoint, we address this challenge and support ongoing initiatives aimed at democratizing natural product data by collating our collective knowledge into a knowledge graph. By doing so, we believe there will be an opportunity to use such a knowledge graph to develop AI models that can truly mimic natural product scientists' decision-making.

Cervical cancer screening among Michigan women: 'The Special Cancer Behavioral Risk Factor Survey', 2004-2008.

The burden of cervical cancer remains greater among minority women. The purpose of this study was to evaluate racial/ethnic disparities in cervical cancer screening among minority women in Michigan. Data from 8,023 women (≥ 40 years) surveyed in the 2004-2008 Michigan Special Cancer Behavioral Risk Factor Survey were used to assess racial/ethnic differences in cervical cancer screening, knowledge and beliefs. Unexpectedly, African-American and Hispanic women reported being screened for cervical cancer at rates similar to, or higher than, Whites. Women demonstrated limited knowledge of cervical cancer risk factors and its signs/symptoms. Most minority women were more likely than Whites to believe in the importance of cervical screening, with Hispanic women more likely to support HPV vaccination. Differential utilisation of screening does not explain the disproportionately high rates of cervical cancer among minorities. Future research should examine disparities in the follow-up of abnormal cervical results and receipt of treatment.

Atrial flutter caused by migration of a superior vena cava stent into the right atrium.

We describe the case of a patient presenting with an atrial flutter mechanically induced by a stent migration from the superior vena cava to the right atrium.

[ICD and left ventricular assist device interference: Case report]. / Interférence électromagnétique entre défibrillateur implantable et dispositif d'assistance circulatoire.

Left ventricular assist devices are used for severe chronic heart failure management. Many of these patients have an implantable cardioverter defibrillator (ICD). However electromagnetic interferences are possible between the 2 devices. We report here a case of an interference in a 77 years-old patient. This was associated with an impossibility to communicate with the ICD. We discuss how to manage this situation.

Exposure-response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn's disease.

BACKGROUND: Therapeutic drug monitoring may optimize therapy for Crohn's disease (CD). AIM: To use a population pharmacokinetic model that accounts for the time-varying nature of covariates to simulate certolizumab pegol (CZP) concentrations to evaluate the exposure-response relationship for CZP in Crohn's disease. METHODS: Adults (N = 2157) with Crohn's disease were treated with CZP in nine clinical trials. Simulated CZP concentrations were compared to outcomes at weeks 6 and 26, including Crohn's disease activity index (CDAI) response (decrease from baseline ≥ 100 points), remission (CDAI ≤ 150), C-reactive protein (CRP) ≤ 5 mg/L, faecal calprotectin (FC) ≤ 250 µg/g, and a composite endpoint of CDAI ≤ 150 and FC ≤ 250 µg/g. Multivariable analyses identified covariates associated with outcomes and receiver operating characteristic analyses determined optimal CZP concentrations. RESULTS: CZP concentrations at weeks 2, 4 and 6 were higher in patients with clinical response, remission, CRP ≤ 5 mg/L or FC ≤ 250 µg/g at week 6 than without. In multivariable analyses, higher CZP concentrations at week 6 were associated with the composite outcome at weeks 6 and 26 (P < .001). Although the exposure-response relationship varied among patients, approximate CZP concentrations of at least 36.1 µg/mL (positive predictive value [PPV] 22.8% and negative predictive value [NPV] 92.7%) and at least 14.8 µg/mL (PPV 28.0% and NPV 90.4%) at weeks 6 and 12 were associated with weeks 6 and 26 outcomes. CONCLUSIONS: An exposure-response relationship was apparent for CZP in Crohn's disease and achieving higher CZP concentrations may increase the likelihood of attaining efficacy outcomes, but this remains to be evaluated prospectively.

Nephropathy in NIDDM is associated with cellular markers for hypertension.

OBJECTIVE: To determine if nephropathy in NIDDM is associated with cellular markers for hypertension. RESEARCH DESIGN AND METHODS: We compared 11 patients with clinical diabetic nephropathy with 15 control subjects with no diabetic nephropathy. The patients were white and had had NIDDM for > or = 9 yr and serum creatinine levels < or = 177 M (2.0 mg/dl). RESULTS: Patients with nephropathy were more obese and had higher blood pressures and triglyceride levels, and lower high-density lipoprotein cholesterol levels than control subjects. Erythrocyte sodium lithium countertransport activity, erythrocyte sodium content, and platelet sodium-proton exchange were higher in patients with nephropathy than in control subjects. CONCLUSIONS: The results of this small study suggest that in white patients with long-standing NIDDM, diabetic nephropathy is associated with cellular markers for hypertension. Measurement of cellular markers for hypertension may be useful to identify patients who are at risk for developing nephropathy.

Determination of phytochemicals and antioxidant activity of methanol extracts obtained from the fruit and leaves of Tunisian Lycium intricatum Boiss.

A comparative analysis of methanol extracts from fruit and leaves of Lycium intricatum Boiss., a Solanaceous shrubbery with the potential to become a high-value crop, was performed by means of liquid chromatography with photodiode array and electrospray ionisation mass spectrometric detection (LC/PDA/ESI-MS). The total phenolic (TPC), anthocyanin (TAC) and flavonoid (TFC) contents as well as the antioxidant capacity measured by four complementary methods were performed for each sample. The results showed the tested extracts to be rich sources of phenolics; in leaves polyphenols and flavonoids dominate, while in fruit anthocyanins dominate. Nineteen phenolic compounds were detected and fifteen were identified or tentatively characterised based on Photodiode-array ultraviolet visible (PDA) UV-Vis spectra, ESI-MS spectrometric data and spiking experiments with authentic standards. Rutin and chlorogenic acid are the major constituents of the leaves and fruit, respectively. Results obtained in this study have revealed that leaves exhibit better performance in all antioxidant assays. From these results it has been shown that extracts of L. intricatum have great potential as a source of phenolics for natural health products.

Allogeneic stem cell transplantation for sickle cell disease. A study of patients' decisions.

Allogeneic stem cell transplantation is increasingly considered as a curative though risky treatment option for adults with sickle cell disease. Little is known about attitudes of adult patients and their health care providers regarding the risks and benefits of transplantation. A survey of 100 patients and their health care providers was undertaken. Assessment of risk was by a reference gamble paradigm. Comparison was made of the characteristics of those accepting substantial risk vs those not accepting risk, as well as assessment of agreement on risks recommended by health care providers and accepted by patients. Sixty-three of 100 patients were willing to accept some short-term risk of mortality in exchange for the certainty of cure. Fifteen patients were willing to accept more than 35% mortality risk. No differences in patient or disease-related variables were identified between those accepting risk and those not accepting risk. There was no agreement between the recommendations of health care providers and the risk accepted by patients. A substantial proportion of adults with sickle cell disease are interested in curative treatment, at the expense of considerable risk. The decision to accept risk is influenced by individual patient values that cannot be easily quantified and that do not correlate with the assessment of the health care provider. Given the substantial interest in curative therapy, education about and consultation for allogeneic stem cell transplantation in sickle cell patients should be encouraged.

Fludarabine and melphalan-based conditioning for patients with advanced hematological malignancies relapsing after a previous hematopoietic stem cell transplant.

Severe regimen-related toxicity often complicates second transplant procedures performed in patients with hematological malignancies that have relapsed after an initial hematopoietic stem cell (HSC) transplant. Therefore, we studied the safety and efficacy of a reduced-intensity fludarabine and melphalan based conditioning regimen in 11 patients who had relapsed following an autologous (n = 7) or allogeneic (n = 4) HSC transplant. All patients received allogeneic peripheral blood HSC from either an HLA-identical (n = 7) or an HLA-mismatched (n = 4) relative. Diagnoses included AML (n = 9), ALL (n = 1), or Hodgkin's disease (n = 1). Only one patient was in complete remission at the time of second transplant. The median interval between first transplant and relapse was 163 days (range 58-1885). Recipients of HLA-mismatched transplants received antithymocyte globulin in addition to fludarabine and melphalan as part of the conditioning regimen. All 11 patients received acute GVHD prophylaxis consisting of tacrolimus and methotrexate. Ten of 11 patients achieved hematopoietic engraftment with a median time to absolute neutrophil count >0.5 x 10(9)/l and to platelet count of >20 x 10(9)/l of 14 and 19 days, respectively. All engrafting patients achieved 100% donor chimerism on initial analysis, except for one with persistent leukemia at day +19. Two patients experienced grade 3 regimen-related toxicity, manifesting as acute renal failure. Acute GVHD grades 2-4 occurred in two recipients and chronic GVHD in four. The 100-day mortality from all causes was 36%. Ten of 11 patients (91%) died a median of 140 days (range 9-996) after the second transplant. The causes of death included relapse (n = 5), sepsis (n = 4), and idiopathic pneumonia syndrome (n = 1). One patient with AML survives in remission at 880 days post-transplant. We conclude that fludarabine- and melphalan-based conditioning promotes full donor chimerism, even following HLA-mismatched transplants. However, the regimen may be more beneficial when applied to patients undergoing allogeneic HSC transplantation earlier in their disease course.

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies.

A total of 31 consecutive patients with hematologic malignancies who were considered poor candidates for TBI underwent allogeneic stem cell transplantation after conditioning with fludarabine and melphalan. A total of 25 matched sibling recipients received fludarabine 25 mg/m(2) x 5 days and melphalan 70 mg/m(2) x 2 days. For unrelated and haploidentical donor recipients, fludarabine was increased to 30 mg/m(2) and ATG 30 mg/kg x 4 days was added. Graft-versus-host disease prophylaxis consisted of tacrolimus and mini methotrexate. All patients engrafted. Regimen-related toxicity was considerable and included mainly renal, hepatic and mucosal toxicity. There were seven regimen-related-deaths including two VOD, two pulmonary, one renal, one cardiac and one mucosal toxicity. One case of fatal pulmonary toxicity death could be attributed to pre-existing pulmonary damage. Progression-free survival at 12 months was 44% (90% CI: 30-58%) for recipients of HLA-identical sibling transplants and 33% (90% CI: 21-45%) for all patients. In conclusion, the fludarabine-melphalan regimen leads to consistent engraftment. The regimen-related toxicity is considerable and cannot be explained solely by patient selection. Cardiac toxicity is emerging as a unique toxicity of this regimen. Despite toxicity, fludarabine-melphalan has considerable activity and leads to durable remission in a proportion of patients.

Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies.

Fludarabine, thiotepa and total body irradiation (TBI) has been used as conditioning in haplo-identical transplantation. We studied this conditioning regimen in adults undergoing matched sibling transplantation and alternative donor transplantation. A total of 30 consecutive patients underwent matched related, haplo-identical related or matched unrelated donor transplantation with fludarabine, thiotepa and TBI conditioning. All but four had advanced hematologic malignancies. For haplo-identical transplant, ATG was added to the regimen. All patients received peripheral blood stem cells; these were T-cell depleted for 2-antigen or 3-antigen mismatched related transplantation. Additional graft-versus-host disease prophylaxis consisted of tacrolimus and mini-methotrexate. One recipient of haplo-identical transplant failed to engraft; all other evaluable patients had prompt engraftment. Four patients died of regimen-related toxicity. In all, 14 additional patients died of regimen-related causes including four from failure to thrive with persistent thrombocytopenia and four from delayed pulmonary toxicity. Six patients relapsed. Progression-free survival at 12 months was 47% (90% CI: 25-69%) for recipients of HLA-identical sibling transplants and 30% (90% CI: 14-46%) for all patients. Five of six long-term survivors have extensive chronic GVHD. As a result of the delayed complications and a relatively high recurrence rate, we abandoned this regimen.

Low incidence of CMV viremia and disease after allogeneic peripheral blood stem cell transplantation. Role of pretransplant ganciclovir and post-transplant acyclovir.

To establish the incidence of CMV viremia after allogeneic blood stem cell transplantation, we studied 51 consecutive allogeneic peripheral blood stem cell (PBSC) transplant recipients. A total of 12 recipients were at moderate risk for CMV disease and 39 were at high risk. Conditioning regimens varied, but GvHD prophylaxis consisted of tacrolimus and mini-methotrexate in all patients. All patients received prophylactic ganciclovir from admission until day -2 and prophylactic acyclovir from day -1 until day 180 after transplantation. CMV viremia was treated with ganciclovir. Using a PCR-based technique, the cumulative incidence of CMV viremia was 31+/-14% by day 100 and 35+/-14% by day 150. Donor type, CMV risk group, underlying disorder, conditioning regimen, GvHD, and steroid use were not associated with the risk for CMV viremia. No cases of CMV disease occurred. We hypothesize that the low rate of CMV viremia and the absence of CMV disease in this cohort of PBSCT transplant recipients, which contrasts with other reports, may be related to the prophylactic use of high-dose acyclovir and possibly to pretransplant use of ganciclovir.

Discrimination between tumour and normal cells by staining with 3,4,5,6,16,17-hexadehydro-16-(methoxycarbonyl)-19 alpha-methyl-20 alpha-oxayohimbanium: the uracil ring as a target for the specific interaction between RNA(s) and the fluorescent probe.

3,4,5,6,16,17-Hexadehydro-16-(methoxycarbonyl)-19 alpha-methyl-20 alpha-oxayohimbanium (Alstonine) is a fluorescent alcaloid which has been known to stain tumour cells more efficiently than normal ones. In this paper the spectral properties of Alstonine were first investigated and its capability for preferential staining of tumour cells verified in culture using SK-OV-3 cells as tumour cells and Mouse 3T3 fibroblasts as controls. Then interactions between Alstonine and biological macromolecules were investigated to provide the rationale for preferential labelling. Molecular filtration techniques have demonstrated that binding occurs only with RNA molecules. Similar experiments were performed with different isopolynucleotides to find an explanation for that specificity. They provide evidence that binding occurs only in the presence of a uridyl ring. This is consistent with the specificity of the linkage to RNA. As the linkage of Alstonine with RNA did not induce any shift or obvious change in the intensity of its fluorescence spectrum, it is concluded that the binding might involve the side chain of the fluorescent compound.

[Successful thrombolysis on an aortic valve prosthesis by plasminogen tissue activator during pregnancy]. / Thrombolyse réussie d'une thrombose de prothèse aortique par activateur tissulaire du plasminogène durant la grossesse. A propos d'un cas.

The authors report the case of a 28 year old woman admitted as an emergency at 15 weeks' amenorrhea for malaise with transient aphasia and orthopnoea due to massive thrombosis of a St Jude aortic valve prosthesis implanted two years previously. This complication occurred after relay of oral anticoagulants with subcutaneous heparin therapy. After a medico-surgical and obstetrical discussion, the indication for thrombolytic therapy with 50 mg of rt-PA over two hours was decided with an excellent clinical and echocardiographic, immediate and lasting result, without any maternal or foetal complication. This enabled pregnancy to be continued to term under oral anti-coagulant therapy. Caesarean section was performed at 8 months leading to the birth of a healthy child. Echocardiographic and radioscopic parameters in the post-partum period showed good prosthetic valve function with no indication for reoperation. This case is original by the absence of neurological and obstetrical complications of thrombolysis, the continuation of pregnancy to term and complete lysis of the thrombus without replacement of the valvular prosthesis.

[Prolongation of the averaged QRS complex. A simple prognostic factor in patients with post-infarction bundle branch block and a history of syncope]. / Prolongation de la durée du QRS moyenné. Elément simple de pronostic des patients avec bloc de branche, séquelle d'infarctus et histoire de malaises.

Patients with a history of myocardial infarction and complete bundle branch block with syncopal episodes have a high risk of sudden death: the identification of the cause of the syncope is therefore essential. The aim of the study was to assess the diagnostic value of non-invasive techniques used in the investigations of syncope: 24 hour Holter recording, high amplification ECG and measurement of left ventricular ejection fraction. The results of these investigations were compared with those of complete electrophysiological investigation evaluating atrioventricular conduction and the inducibility of tachycardia. The patient population was 134 patients, 83 with right bundle branch block and 51 with left bundle branch block. Ninety one patients had inducible sustained ventricular tachycardia and 24 had atrioventricular conduction defects: of these, 14 also had ventricular tachycardia. During follow-up, there were 12 sudden deaths and 13 deaths from cardiac failure. Uni- and multivariate analysis showed induction of ventricular tachycardia to be a significant risk factor for global mortality and sudden death but prolongation of the averaged QRS complex (> 165 msec) was also an independent risk factor of global cardiac mortality. The authors conclude that simple prolongation of the averaged QRS duration > 160 ms in patients with right bundle branch block and > 170 ms in patients with left bundle branch block after myocardial infarction and syncope is a significant poor prognostic factor. However, this sign is not predictive of sudden death.

[Can the supraventricular proarrhythmic effects of class 1C antiarrhythmic drugs be prevented with the association of beta blockers?]. / Les effets proarythmiques supraventricúlaires des antiarythmiques de classe IC sont-ils prévenus par l'association avec des bêtabloquants?

Due to their electrophysiological characteristics, class 1 antiarrhythmic drugs can induce an auricular flutter with a 1/1 response. In addition to antiarrhythmic treatment, several authors have therefore considered using drugs capable of slowing auriculoventricular nodal conduction and preventing the 1/1 response. Beta-blockers have been proposed as candidate drugs. In this study, two patients were treated with an association of class 1 antiarrhythmic drugs (cibenzoline in one case, flecainide in the other) and beta-blockers. The administration of these drugs resulted in an atrial proarrhythmic response, and wide QRS tachycardia. Although both subjects had underlying heart disease, the tachycardia was relatively well tolerated in both instances. It was concluded that although beta-blockers may not suppress the risk of atrial proarrhythmia, they at least permit an improved tolerance to this complication.

Identification of ML-9 as a lysosomotropic agent targeting autophagy and cell death.

The growing number of studies suggested that inhibition of autophagy enhances the efficacy of Akt kinase inhibitors in cancer therapy. Here, we provide evidence that ML-9, a widely used inhibitor of Akt kinase, myosin light-chain kinase (MLCK) and stromal interaction molecule 1 (STIM1), represents the 'two-in-one' compound that stimulates autophagosome formation (by downregulating Akt/mammalian target of rapamycin (mTOR) pathway) and inhibits their degradation (by acting like a lysosomotropic agent and increasing lysosomal pH). We show that ML-9 as a monotherapy effectively induces prostate cancer cell death associated with the accumulation of autophagic vacuoles. Further, ML-9 enhances the anticancer activity of docetaxel, suggesting its potential application as an adjuvant to existing anticancer chemotherapy. Altogether, our results revealed the complex effect of ML-9 on autophagy and indentified ML-9 as an attractive tool for targeting autophagy in cancer therapy through dual inhibition of both the Akt pathway and the autophagy.