Structural basis for the intracellular regulation of ferritin degradation.

The interaction between nuclear receptor coactivator 4 (NCOA4) and the iron storage protein ferritin is a crucial component of cellular iron homeostasis. The binding of NCOA4 to the FTH1 subunits of ferritin initiates ferritinophagy-a ferritin-specific autophagic pathway leading to the release of the iron stored inside ferritin. The dysregulation of NCOA4 is associated with several diseases, including neurodegenerative disorders and cancer, highlighting the NCOA4-ferritin interface as a prime target for drug development. Here, we present the cryo-EM structure of the NCOA4-FTH1 interface, resolving 16 amino acids of NCOA4 that are crucial for the interaction. The characterization of mutants, designed to modulate the NCOA4-FTH1 interaction, is used to validate the significance of the different features of the binding site. Our results explain the role of the large solvent-exposed hydrophobic patch found on the surface of FTH1 and pave the way for the rational development of ferritinophagy modulators.

Activation of alkyl hydroperoxides by manganese complexes of tmtacn for initiation of radical polymerisation of alkenes.

The activation of alkyl hydroperoxides to generate radicals is a key step in the initiation of radical polymerisations in many industrial applications, not least protective coatings. Cobalt soaps (Co(ii) alkyl carboxylates) are highly effective catalysts under ambient conditions but viable alternatives based on less scarce catalysts are desirable, with especially iron and manganese catalysts showing potential. Manganese complexes of the ligand N,N',N″-trimethyl-1,4,7-triazacyclononane (tmtacn) are long established as catalysts for organic oxidations with H2O2, however their reactivity with alkyl hydroperoxides is less studied especially in apolar solvents. Here we show that this family of complexes can be employed as catalysts for the decomposition of alkyl hydroperoxides in apolar solvents such as styrene/methyl methacrylate mixtures and resins based on styrene/bisphenol-A based diglycidyl ether bismethacrylate (BADGE-MA). The progress of alkene polymerisation in crosslinking resins is followed by Raman spectroscopy to establish its dependence on the oxidation state of the manganese catalyst used, as gelation time and onset of autoacceleration are of particular interest for many applications. We show, through reaction progress monitoring with UV/vis absorption and Raman spectroscopy, that the stability of the manganese complexes in the resin mixtures has a substantial effect on curing progress and that the oxidation state of the resting state of the catalyst is most likely Mn(ii), in contrast to reactions with H2O2 as oxidant in which the oxidation state of the resting state of catalyst is Mn(iii). Manganese complexes of tmtacn are shown to be capable initiators of alkene radical polymerisations, and their rich coordination and redox chemistry means that resin curing kinetics can potentially be tuned more readily than with cobalt alkyl carboxylates.

Correlation of microscopic tumor extension with tumor microenvironment in esophageal cancer patients.

OBJECTIVE: In the era of image-guided adaptive radiotherapy, definition of the clinical target volume (CTV) is a challenge in various solid tumors, including esophageal cancer (EC). Many tumor microenvironmental factors, e.g., tumor cell proliferation or cancer stem cells, are hypothesized to be involved in microscopic tumor extension (MTE). Therefore, this study assessed the expression of FAK, ILK, CD44, HIF-1α, and Ki67 in EC patients after neoadjuvant radiochemotherapy followed by tumor resection (NRCHT+R) and correlated these markers with the MTE. METHODS: Formalin-fixed paraffin-embedded tumor resection specimens of ten EC patients were analyzed using multiplex immunofluorescence staining. Since gold fiducial markers had been endoscopically implanted at the proximal and distal tumor borders prior to NRCHT+R, correlation of the markers with the MTE was feasible. RESULTS: In tumor resection specimens of EC patients, the overall percentages of FAK+, CD44+, HIF-1α+, and Ki67+ cells were higher in tumor nests than in the tumor stroma, with the outcome for Ki67+ cells reaching statistical significance (p < 0.001). Conversely, expression of ILK+ cells was higher in tumor stroma, albeit not statistically significantly. In three patients, MTE beyond the fiducial markers was found, reaching up to 31 mm. CONCLUSION: Our findings indicate that the overall expression of FAK, HIF-1α, Ki67, and CD44 was higher in tumor nests, whereas that of ILK was higher in tumor stroma. Differences in the TME between patients with residual tumor cells in the original CTV compared to those without were not found. Thus, there is insufficient evidence that the TME influences the required CTV margin on an individual patient basis. TRIAL REGISTRATION NUMBER AND DATE: BO-EK-148042017 and BO-EK-177042022 on 20.06.2022, DRKS00011886, https://drks.de/search/de/trial/DRKS00011886 .

Early Administration of Intravenous Hydration and Opioid Analgesics Is Correlated with Decreased Admission Rates during Vaso-Occlusive Episodes in Sickle Cell Disease.

Background: Painful vaso-occlusive episodes (VOEs) are the hallmark of sickle cell disease (SCD) and account for frequent visits to the emergency department (ED) or urgent care (UC). Currently, the early administration of analgesics is recommended as initial management; however, there is a need for further understanding of the effect of prompt analgesics and hydration during VOEs. The objective of this study is to analyze the factors associated with the rate of hospital admission in the setting of time to intravenous (IV) analgesics and hydration. Method: This retrospective single-institution study reviewed adult and pediatric patients with SCD who presented with VOEs from January 2018 to August 2023. Results: Of 303 patient encounters, the rates of admission for the overall group, the subgroup which received IV hydration within 60 min of arrival, and the subgroup which received both IV analgesics and hydration within 60 min were 51.8%, 25.6% (RR = 0.46), and 18.2% (RR = 0.33), respectively. Further, factors such as gender and the use of hydroxyurea were found to be significantly associated with the rate of admission. Conclusions: This signifies the importance of standardizing the management of VOEs through the timely administration of IV analgesics and hydration in both adult and pediatric ED/UC.

Automatic Segmentation of Abdominal Aortic Aneurysms from Time-Resolved 3D Ultrasound Images Using Deep Learning.

Abdominal aortic aneurysms (AAAs) are rupture-prone dilatations of the aorta. In current clinical practice, the maximal diameter of AAAs is monitored with 2D ultrasound to estimate their rupture risk. Recent studies have shown that 3-dimensional and mechanical AAA parameters might be better predictors for aneurysm growth and rupture than the diameter. These parameters can be obtained with time-resolved 3D ultrasound (3D+t US), which requires robust and automatic segmentation of AAAs from 3D+t US. This study proposes and validates a deep learning (DL) approach for automatic segmentation of AAAs. 500 AAA patients were included for follow-up 3D+t US imaging, resulting in 2495 3D+t US images. Segmentation masks for model training were obtained using a conventional automatic segmentation algorithm ('nonDL'). Four different DL models were trained and validated by (1) comparison to CT and (2) reader scoring. Performance of the nonDL and different DL segmentation strategies were evaluated by comparing Hausdorff distance, Dice scores, accuracy, sensitivity, and specificity with a sign test. All DL models had higher median Dice scores, accuracy, and sensitivity (all p < 0.003) compared to nonDL segmentation. The full image-resolution model without data augmentation showed the highest median Dice score and sensitivity (p < 0.001). Applying the DL model on an independent test group produced fewer poor segmentation scores of 1 to 2 on a five-point scale (8% for DL, 18% for nonDL). This demonstrates that a robust and automatic segmentation algorithm for segmenting abdominal aortic aneurysms from 3D+t US images was developed, showing improved performance compared to conventional segmentation.

Towards a European prospective data registry for particle therapy.

The evidence for the value of particle therapy (PT) is still sparse. While randomized trials remain a cornerstone for robust comparisons with photon-based radiotherapy, data registries collecting real-world data can play a crucial role in building evidence for new developments. This Perspective describes how the European Particle Therapy Network (EPTN) is actively working on establishing a prospective data registry encompassing all patients undergoing PT in European centers. Several obstacles and hurdles are discussed, for instance harmonization of nomenclature and structure of technical and dosimetric data and data protection issues. A preferred approach is the adoption of a federated data registry model with transparent and agile governance to meet European requirements for data protection, transfer, and processing. Funding of the registry, especially for operation after the initial setup process, remains a major challenge.

Perceived Challenges to Tribally Led Shellfish Toxin Testing in Southeast Alaska: Findings From Key Informant Interviews.

Shellfish harvesting is central to coastal Alaska Native ways of life, and tribes in Southeast Alaska are committed to preserving sustainable and safe access to subsistence foods. However, consumption of non-commercially harvested shellfish puts Alaska Native communities at elevated risk of exposure to shellfish toxins. To address a lack of state or federal toxin testing for subsistence and recreational harvesting, tribes across Southeast Alaska have formed their own toxin testing and ocean monitoring program. In this study, we interviewed environmental managers responsible for tribes' testing and others with shellfish toxin expertise to report on perceptions of barriers to tribally led testing in Southeast Alaska. Tribal staff identified 40 prospective key informants to interview, including all environmental managers responsible for shellfish toxin testing at subsistence sites in Southeast Alaska. All 40 individuals were invited to participate in an interview and 27 individuals were interviewed. The most frequently discussed barriers to shellfish toxin testing in Southeast Alaska relate to logistical and staffing difficulties associated with communities' remote locations, inconsistent and inadequate funding and funding structures that increase staff burdens, risk communication challenges related to conveying exposure risks while supporting subsistence harvesting, and implications of climate change-related shifts in toxin exposures for risk perception and risk communication. Participants stressed the social origins of perceived barriers. Disinvestment may create and sustain barriers and be most severely felt in Native communities and remote places. Climate change impacts may interact with social and cultural factors to further complicate risk management.

Partitioning and Mobility of Chromium in Iron-Rich Laterites from an Optimized Sequential Extraction Procedure.

Chromium (Cr) leached from iron (Fe) (oxyhydr)oxide-rich tropical laterites can substantially impact downstream groundwater, ecosystems, and human health. However, its partitioning into mineral hosts, its binding, oxidation state, and potential release are poorly defined. This is in part due to the current lack of well-designed and validated Cr-specific sequential extraction procedures (SEPs) for laterites. To fill this gap, we have (i) first optimized a Cr SEP for Fe (oxyhydr)oxide-rich laterites using synthetic and natural Cr-bearing minerals and laterite references, (ii) used a complementary suite of techniques and critically evaluated existing non-laterite and non-Cr-optimized SEPs, compared to our optimized SEP, and (iii) confirmed the efficiency of our new SEP through analyses of laterites from the Philippines. Our results show that other SEPs inadequately leach Cr host phases and underestimate the Cr fractions. Our SEP recovered up to seven times higher Cr contents because it (a) more efficiently dissolves metal-substituted Fe phases, (b) quantitatively extracts adsorbed Cr, and (c) prevents overestimation of organic Cr in laterites. With this new SEP, we can estimate the mineral-specific Cr fractionation in Fe-rich tropical soils more quantitatively and thus improve our knowledge of the potential environmental impacts of Cr from lateritic areas.

A chloromethyl-triazole fluorescent chemosensor for O6-methylguanine DNA methyltransferase.

Fluorescent chemosensors offer a direct means of measuring enzyme activity for cancer diagnosis, predicting drug resistance, and aiding in the discovery of new anticancer drugs. O6-methylguanine DNA methyltransferase (MGMT) is a predictor of resistance towards anticancer alkylating agents such as temozolomide. Using the fluorescent molecular rotor, 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ), we synthesized, and evaluated a MGMT fluorescent chemosensor derived from a chloromethyl-triazole covalent inhibitor, AA-CW236, a non-pseudosubstrate of MGMT. Our fluorescence probe covalently labelled the MGMT active site C145, producing a 18-fold increase in fluorescence. Compared to previous fluorescent probes derived from a substrate-based inhibitor, our probe had improved binding and reaction rate. Overall, our chloromethyl triazole-based fluorescence MGMT probe is a promising tool for measuring MGMT activity to predict temozolomide resistance.

Sensitivity and consistency of long- and short-read metagenomics and epicPCR for the detection of antibiotic resistance genes and their bacterial hosts in wastewater.

Wastewater surveillance is a powerful tool to assess the risks associated with antibiotic resistance in communities. One challenge is selecting which analytical tool to deploy to measure risk indicators, such as antibiotic resistance genes (ARGs) and their respective bacterial hosts. Although metagenomics is frequently used for analyzing ARGs, few studies have compared the performance of long-read and short-read metagenomics in identifying which bacteria harbor ARGs in wastewater. Furthermore, for ARG host detection, untargeted metagenomics has not been compared to targeted methods such as epicPCR. Here, we 1) evaluated long-read and short-read metagenomics as well as epicPCR for detecting ARG hosts in wastewater, and 2) investigated the host range of ARGs across the wastewater treatment plant (WWTP) to evaluate host proliferation. Results highlighted long-read revealed a wider range of ARG hosts compared to short-read metagenomics. Nonetheless, the ARG host range detected by long-read metagenomics only represented a subset of the hosts detected by epicPCR. The ARG-host linkages across the influent and effluent of the WWTP were characterized. Results showed the ARG-host phylum linkages were relatively consistent across the WWTP, whereas new ARG-host species linkages appeared in the WWTP effluent. The ARG-host linkages of several clinically relevant species found in the effluent were identified.

Radiomics for residual tumour detection and prognosis in newly diagnosed glioblastoma based on postoperative [11C] methionine PET and T1c-w MRI.

Personalized treatment strategies based on non-invasive biomarkers have potential to improve patient management in patients with newly diagnosed glioblastoma (GBM). The residual tumour burden after surgery in GBM patients is a prognostic imaging biomarker. However, in clinical patient management, its assessment is a manual and time-consuming process that is at risk of inter-rater variability. Furthermore, the prediction of patient outcome prior to radiotherapy may identify patient subgroups that could benefit from escalated radiotherapy doses. Therefore, in this study, we investigate the capabilities of traditional radiomics and 3D convolutional neural networks for automatic detection of the residual tumour status and to prognosticate time-to-recurrence (TTR) and overall survival (OS) in GBM using postoperative [11C] methionine positron emission tomography (MET-PET) and gadolinium-enhanced T1-w magnetic resonance imaging (MRI). On the independent test data, the 3D-DenseNet model based on MET-PET achieved the best performance for residual tumour detection, while the logistic regression model with conventional radiomics features performed best for T1c-w MRI (AUC: MET-PET 0.95, T1c-w MRI 0.78). For the prognosis of TTR and OS, the 3D-DenseNet model based on MET-PET integrated with age and MGMT status achieved the best performance (Concordance-Index: TTR 0.68, OS 0.65). In conclusion, we showed that both deep-learning and conventional radiomics have potential value for supporting image-based assessment and prognosis in GBM. After prospective validation, these models may be considered for treatment personalization.

Impact of COVID-19 on Perinatal Outcomes and Birth Locations in a Large US Metropolitan Area.

This was a population-based study to determine the impact of COVID-19 on birth outcomes in the Chicago metropolitan area, comparing pre-pandemic (April-September 2019) versus pandemic (April-September 2020) births. Multivariable regression models that adjusted for demographic and neighborhood characteristics were used to estimate the marginal effects of COVID-19 on intrauterine fetal demise (IUFD)/stillbirth, preterm birth, birth hospital designation, and maternal and infant hospital length of stay (LOS). There were no differences in IUFD/stillbirths or preterm births between eras. Commercially insured preterm and term infants were 4.8 percentage points (2.3, 7.4) and 3.4 percentage points (2.5, 4.2) more likely to be born in an academic medical center during the pandemic, while Medicaid-insured preterm and term infants were 3.6 percentage points less likely (-6.5, -0.7) and 1.8 percentage points less likely (-2.8, -0.9) to be born in an academic medical center compared to the pre-pandemic era. Infant LOS decreased from 2.4 to 2.2 days (-0.35, -0.20), maternal LOS for indicated PTBs decreased from 5.6 to 5.0 days (-0.94, -0.19), and term births decreased from 2.5 to 2.3 days (-0.21, -0.17). The pandemic had a significant effect on the location of births that may have exacerbated health inequities that continue into childhood.

Iron regulatory proteins 1 and 2 have opposing roles in regulating inflammation in bacterial orchitis.

Acute bacterial orchitis (AO) is a prevalent cause of intrascrotal inflammation, often resulting in sub- or infertility. A frequent cause eliciting AO is uropathogenic Escherichia coli (UPEC), a gram negative pathovar, characterized by the expression of various iron acquisition systems to survive in a low-iron environment. On the host side, iron is tightly regulated by iron regulatory proteins 1 and 2 (IRP1 and -2) and these factors are reported to play a role in testicular and immune cell function; however, their precise role remains unclear. Here, we showed in a mouse model of UPEC-induced orchitis that the absence of IRP1 results in less testicular damage and a reduced immune response. Compared with infected wild-type (WT) mice, testes of UPEC-infected Irp1-/- mice showed impaired ERK signaling. Conversely, IRP2 deletion led to a stronger inflammatory response. Notably, differences in immune cell infiltrations were observed among the different genotypes. In contrast with WT and Irp2-/- mice, no increase in monocytes and neutrophils was detected in testes of Irp1-/- mice upon UPEC infection. Interestingly, in Irp1-/- UPEC-infected testes, we observed an increase in a subpopulation of macrophages (F4/80+CD206+) associated with antiinflammatory and wound-healing activities compared with WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signaling and dampening the immune response.

Tight-Binding Small-Molecule Carboxylesterase 2 Inhibitors Reduce Intracellular Irinotecan Activation.

As the primary enzyme responsible for the activatable conversion of Irinotecan (CPT-11) to SN-38, carboxylesterase 2 (CES2) is a significant predictive biomarker toward CPT-11-based treatments for pancreatic ductal adenocarcinoma (PDAC). High SN-38 levels from high CES2 activity lead to harmful effects, including life-threatening diarrhea. While alternate strategies have been explored, CES2 inhibition presents an effective strategy to directly alter the pharmacokinetics of CPT-11 conversion, ultimately controlling the amount of SN-38 produced. To address this, we conducted a high-throughput screening to discover 18 small-molecule CES2 inhibitors. The inhibitors are validated by dose-response and counter-screening and 16 of these inhibitors demonstrate selectivity for CES2. These 16 inhibitors inhibit CES2 in cells, indicating cell permeability, and they show inhibition of CPT-11 conversion with the purified enzyme. The top five inhibitors prohibited cell death mediated by CPT-11 when preincubated in PDAC cells. Three of these inhibitors displayed a tight-binding mechanism of action with a strong binding affinity.

Benzodiazepine use and risk of incident MCI and dementia in a community sample.

OBJECTIVES: Older adults commonly take benzodiazepines (BZDs) that may have long-term adverse cognitive effects. We investigated whether BZD use was related to developing mild cognitive impairment (MCI) or dementia in cognitively normal older adults in the community. SETTING/PARTICIPANTS: A population-based cohort (n = 1959) of adults aged 65 and over, recruited from communities of low socioeconomic status. MEASUREMENTS: BZD use, Clinical Dementia Rating (CDR), anxiety symptoms, depression symptoms, sleep difficulties, and APOE genotype. DESIGN: We examined time from study entry to MCI (CDR = 0.5) and time from study entry to dementia (CDR ≥ 1) in participants who were cognitively normal at baseline (CDR = 0). We used survival analysis (Cox model), adjusted for age, sex, education, sleep, anxiety, and depression. For all the models, we included an interaction term between BZD use and APOE*4. RESULTS: Taking BZDs was significantly associated with higher risk of developing MCI, but not of developing dementia. The effect was not affected by APOE genotype. CONCLUSIONS: In a population-based sample of cognitively normal older adults, BZD use is associated with developing MCI, but not dementia. BZD use may be a potentially modifiable risk factor for MCI.

Prediction of radiation pneumonitis using the effective α/ß of lungs and heart in NSCLC patients treated with proton beam therapy.

PURPOSE: Radiation pneumonitis (RP) remains a major complication in non-small cell lung cancer (NSCLC) patients undergoing radiochemotherapy (RCHT). Traditionally, the mean lung dose (MLD) and the volume of the total lung receiving at least 20 Gy (V20Gy) are used to predict RP in patients treated with normo-fractionated photon therapy. However, other models, including the actual dose-distribution in the lungs using the effective α/ß model or a combination of radiation doses to the lungs and heart, have been proposed for predicting RP. Moreover, the models established for photons may not hold for patients treated with passively-scattered proton therapy (PSPT). Therefore, we here tested and validated novel predictive parameters for RP in NSCLC patient treated with PSPT. METHODS: Data on the occurrence of RP, structure files and dose-volume histogram parameters for lungs and heart of 96 NSCLC patients, treated with PSPT and concurrent chemotherapy, was retrospectively retrieved from prospective clinical studies of two international centers. Data was randomly split into a training set (64 patients) and a validation set (32 patients). Statistical analyses were performed using binomial logistic regression. RESULTS: The biologically effective dose (BED) of the'lungs - GTV' significantly predicted RP ≥ grade 2 in the training-set using both a univariate model (p = 0.019, AUCtrain = 0.72) and a multivariate model in combination with the effective α/ß parameter of the heart (pBED = 0.006, [Formula: see text] = 0.043, AUCtrain = 0.74). However, these results did not hold in the validation-set (AUCval = 0.52 andAUCval = 0.50, respectively). Moreover, these models were found to neither outperform a model built with the MLD (p = 0.015, AUCtrain = 0.73, AUCval = 0.51), nor a multivariate model additionally including the V20Gy of the heart (pMLD = 0.039, pV20Gy,heart = 0.58, AUCtrain = 0.74, AUCval = 0.53). CONCLUSION: Using the effective α/ß parameter of the lungs and heart we achieved similar performance to commonly used models built for photon therapy, such as MLD, in predicting RP ≥ grade 2. Therefore, prediction models developed for photon RCHT still hold for patients treated with PSPT.

A newly identified ferritin L-subunit variant results in increased proteasomal subunit degradation, impaired complex assembly, and severe hypoferritinemia.

Ferritin is a hetero-oligomeric nanocage, composed of 24 subunits of two types, FTH1 and FTL. It protects the cell from excess reactive iron, by storing iron in its cavity. FTH1 is essential for the recruitment of iron into the ferritin nanocage and for cellular ferritin trafficking, whereas FTL contributes to nanocage stability and iron nucleation inside the cavity. Here we describe a female patient with a medical history of severe hypoferritinemia without anemia. Following inadequate heavy IV iron supplementation, the patient developed severe iron overload and musculoskeletal manifestations. However, her serum ferritin levels rose only to normal range. Genetic analyses revealed an undescribed homozygous variant of FTL (c.92A > G), which resulted in a Tyr31Cys substitution (FTLY31C ). Analysis of the FTL structure predicted that the Y31C mutation will reduce the variant's stability. Expression of the FTLY31C variant resulted in significantly lower cellular ferritin levels compared with the expression of wild-type FTL (FTLWT ). Proteasomal inhibition significantly increased the initial levels of FTLY31C , but could not protect FTLY31C subunits from successive degradation. Further, variant subunits successfully incorporated into hetero-polymeric nanocages in the presence of sufficient levels of FTH1. However, FTLY31C subunits poorly assembled into nanocages when FTH1 subunit levels were low. These results indicate an increased susceptibility of unassembled monomeric FTLY31C subunits to proteasomal degradation. The decreased cellular assembly of FTLY31C -rich nanocages may explain the low serum ferritin levels in this patient and emphasize the importance of a broader diagnostic approach of hypoferritinemia without anemia, before IV iron supplementation.

A Phase 1 Study of the DNA-PK Inhibitor Peposertib in Combination With Radiation Therapy With or Without Cisplatin in Patients With Advanced Head and Neck Tumors.

PURPOSE: DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double strand breaks via nonhomologous end joining. Inhibition of DNA-PK can enhance the effect of DNA double strand break inducing anticancer therapies. Peposertib (formerly "M3814") is an orally administered, potent, and selective small molecule DNA-PK inhibitor that has demonstrated radiosensitizing and antitumor activity in xenograft models and was well-tolerated in monotherapy. This phase 1 trial (National Clinical Trial 02516813) investigated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and tolerability of peposertib in combination with palliative radiation therapy (RT) in patients with thoracic or head and neck tumors (arm A) and of peposertib in combination with cisplatin and curative-intent RT in patients with squamous cell carcinoma of the head and neck (arm B). METHODS AND MATERIALS: Patients received peposertib once daily in ascending dose cohorts as a tablet or capsule in combination with palliative RT (arm A) or in combination with intensity modulated curative-intent RT and cisplatin (arm B). RESULTS: The most frequently observed treatment-emergent adverse events were radiation skin injury, fatigue, and nausea in arm A (n = 34) and stomatitis, nausea, radiation skin injury, and dysgeusia in arm B (n = 11). Based on evaluations of dose-limiting toxicities, tolerability, and pharmacokinetic data, RP2D for arm A was declared as 200 mg peposertib tablet once daily in combination with RT. In arm B (n = 11), 50 mg peposertib was declared tolerable in combination with curative-intent RT and cisplatin. However, enrollment was discontinued because of insufficient exposure at that dose, and the RP2D was not formally declared. CONCLUSIONS: Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg once daily as tablet with each RT fraction. When combined with RT and cisplatin, a tolerable peposertib dose yielded insufficient exposure.

Enantioselective Hydrophosphination of Terminal Alkenyl Aza-Heteroarenes.

This paper presents a Mn(I)-catalysed methodology for the enantioselective hydrophosphination of terminal alkenyl aza-heteroarenes. The catalyst operates through H-P bond activation, enabling successful hydrophosphination of a diverse range of alkenyl-heteroarenes with high enantioselectivity. The presented protocol addresses the inherently low reactivity and the commonly encountered suboptimal enantioselectivities of these challenging substrates. As an important application we show that this method facilitates the synthesis of a non-symmetric tridentate P,N,P-containing ligand like structure in just two synthetic steps using a single catalytic system.