Cmai: Predicting Antigen-Antibody Interactions from Massive Sequencing Data.

The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.

Interface and Morphology Engineered Amorphous Si for Ultrafast Electrochemical Lithium Storage.

Ultrafast high-capacity lithium-ion batteries are extremely desirable for portable electronic devices, where Si is the most promising alternative to the conventional graphite anode due to its very high theoretical capacity. However, the low electronic conductivity and poor Li-diffusivity limit its rate capability. Moreover, high volume expansion/contraction upon Li-intake/uptake causes severe pulverization of the electrode, leading to drastic capacity fading. Here, interface and morphology-engineered amorphous Si matrix is being reported utilizing a few-layer vertical graphene (VG) buffer layer to retain high capacity at both slow and fast (dis)charging rates. The flexible mechanical support of VG due to the van-der-Waals interaction between the graphene layers, the weak adhesion between Si and graphene, and the highly porous geometry mitigated stress, while the three-dimensional mass loading enhanced specific capacity. Additionally, the high electronic conductivity of VG boosted rate-capability, resulting in a reversible gravimetric capacity of ≈1270 mAh g-1 (areal capacity of ≈37 µAh cm-2) even after 100 cycles at an ultrafast cycling rate of 20C, which provides a fascinating way for conductivity and stress management to obtain high-performance storage devices.

pan-MHC and cross-Species Prediction of T Cell Receptor-Antigen Binding.

Profiling the binding of T cell receptors (TCRs) of T cells to antigenic peptides presented by MHC proteins is one of the most important unsolved problems in modern immunology. Experimental methods to probe TCR-antigen interactions are slow, labor-intensive, costly, and yield moderate throughput. To address this problem, we developed pMTnet-omni, an Artificial Intelligence (AI) system based on hybrid protein sequence and structure information, to predict the pairing of TCRs of αß T cells with peptide-MHC complexes (pMHCs). pMTnet-omni is capable of handling peptides presented by both class I and II pMHCs, and capable of handling both human and mouse TCR-pMHC pairs, through information sharing enabled this hybrid design. pMTnet-omni achieves a high overall Area Under the Curve of Receiver Operator Characteristics (AUROC) of 0.888, which surpasses competing tools by a large margin. We showed that pMTnet-omni can distinguish binding affinity of TCRs with similar sequences. Across a range of datasets from various biological contexts, pMTnet-omni characterized the longitudinal evolution and spatial heterogeneity of TCR-pMHC interactions and their functional impact. We successfully developed a biomarker based on pMTnet-omni for predicting immune-related adverse events of immune checkpoint inhibitor (ICI) treatment in a cohort of 57 ICI-treated patients. pMTnet-omni represents a major advance towards developing a clinically usable AI system for TCR-pMHC pairing prediction that can aid the design and implementation of TCR-based immunotherapeutics.

Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer.

OBJECTIVES: AXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prognosis in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324), a selective orally bioavailable small molecule AXL inhibitor, synergizes with docetaxel in preclinical models. We performed a phase I trial of bemcentinib plus docetaxel in previously treated advanced NSCLC. MATERIALS AND METHODS: Escalation of two dose levels of bemcentinib (200 mg load × 3 days then 100 mg daily, or 400 mg load × 3 days then 200 mg daily) in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a 3+3 study design. Due to hematologic toxicity, prophylactic G-CSF was added. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharmacokinetic effects alone and in combination. Plasma protein biomarker levels were measured. RESULTS: 21 patients were enrolled (median age 62 years, 67% male). Median treatment duration was 2.8 months (range 0.7-10.9 months). The main treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (57%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60 mg/m2 with prophylactic G-CSF support plus bemcentinib 400 mg load × 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharmacokinetics resembled prior monotherapy data. Among 17 patients evaluable for radiographic response, 6 (35%) patients had partial response and 8 (47%) patients had stable disease as best response. Bemcentinib administration was associated with modulation of proteins involved in protein kinase B signaling, reactive oxygen species metabolism, and other processes. CONCLUSION: Bemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation.

Short-term Treatment Outcome of Patients with Acute ST-elevation Myocardial Infarction in a Tertiary Care Hospital.

Outcome of acute ST-elevation myocardial infarction patients varies time to time. The present study was intended to find out the short-term treatment outcome of the patients admitted in hospital. This descriptive study was carried out in Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from 15 January 2014 to 14 July 2014. A total of 100 patients admitted with Acute ST-elevation Myocardial Infarction confirmed on the presence of the (a) Typical chest pain of acute ST-elevation Myocardial Infarction (b) Electrocardiogram (ECG) evidence of ST segment elevation in two or more contiguous leads (c) Raised cardiac marker (Troponin I) were included in the study. Patients were randomly enrolled according to the inclusion and exclusion criteria and observe for one week. Data were processed and analyzed by using computer bases software SPSS version 19.0. Descriptive statistical methods were applied for data analysis. P value was considered as statistically significant when it is less than 0.05. Short-term treatment outcome of acute ST-elevation myocardial infarction include mechanical, arrhythmic, ischemic and inflammatory sequelae, as well as left ventricular mural thrombus. In addition to these broad categories, heart failure, arrhythmia, death are other common complications of AMI. The initiation of the complications usually results in explicit sign and symptoms of the acute MI patients. Learning of the complications in the post infarction period and the clinical syndromes develop with each complication, will allow the health care worker to evaluate and manage the complication appropriately.

Electrostatic Gating of Monolayer Graphene by Concentrated Aqueous Electrolytes.

Electrostatic gating using electrolytes is a powerful approach for controlling the electronic properties of atomically thin two-dimensional materials such as graphene. However, the role of the ionic type, size, and concentration and the resulting gating efficiency is unclear due to the complex interplay of electrochemical processes and charge doping. Understanding these relationships facilitates the successful design of electrolyte gates and supercapacitors. To that end, we employ in situ Raman microspectroscopy combined with electrostatic gating using various concentrated aqueous electrolytes. We show that while the ionic type and concentration alter the initial doping state of graphene, they have no measurable influence over the rate of the doping of graphene with applied voltage in the high ionic strength limit of 3-15 M. Crucially, unlike for conventional dielectric gates, a large proportion of the applied voltage contributes to the Fermi level shift of graphene in concentrated electrolytes. We provide a practical overview of the doping efficiency for different gating systems.

Isotope Engineered Fluorinated Single and Bilayer Graphene: Insights into Fluorination Selectivity, Stability, and Defect Passivation.

Tailoring the physicochemical properties of graphene through functionalization remains a major interest for next-generation technological applications. However, defect formation due to functionalization greatly endangers the intrinsic properties of graphene, which remains a serious concern. Despite numerous attempts to address this issue, a comprehensive analysis has not been conducted. This work reports a two-step fluorination process to stabilize the fluorinated graphene and obtain control over the fluorination-induced defects in graphene layers. The structural, electronic and isotope-mass-sensitive spectroscopic characterization unveils several not-yet-resolved facts, such as fluorination sites and CF bond stability in partially-fluorinated graphene (F-SLG). The stability of fluorine has been correlated to fluorine co-shared between two graphene layers in fluorinated-bilayer-graphene (F-BLG). The desorption energy of co-shared fluorine is an order of magnitude higher than the CF bond energy in F-SLG due to the electrostatic interaction and the inhibition of defluorination in the F-BLG. Additionally, F-BLG exhibits enhanced light-matter interaction, which has been utilized to design a proof-of-concept field-effect phototransistor that produces high photocurrent response at a time <200 µs. Thus, the study paves a new avenue for the in-depth understanding and practical utilization of fluorinated graphenic carbon.

Electrical Contact Resistance of Large-Area Graphene on Pre-Patterned Cu and Au Electrodes.

Contact resistance between electrically connected parts of electronic elements can negatively affect their resulting properties and parameters. The contact resistance is influenced by the physicochemical properties of the connected elements and, in most cases, the lowest possible value is required. The issue of contact resistance is also addressed in connection with the increasingly frequently used carbon allotropes. This work aimed to determine the factors that influence contact resistance between graphene prepared by chemical vapour deposition and pre-patterned Cu and Au electrodes onto which graphene is subsequently transferred. It was found that electrode surface treatment methods affect the resistance between Cu and graphene, where contact resistance varied greatly, with an average of 1.25 ± 1.54 kΩ, whereas for the Au electrodes, the deposition techniques did not influence the resulting contact resistance, which decreased by almost two orders of magnitude compared with the Cu electrodes, to 0.03 ± 0.01 kΩ.

The Effects of Ultrasound Treatment of Graphite on the Reversibility of the (De)Intercalation of an Anion from Aqueous Electrolyte Solution.

Low cycling stability is one of the most crucial issues in rechargeable batteries. Herein, we study the effects of a simple ultrasound treatment of graphite for the reversible (de)intercalation of a ClO4- anion from a 2.4 M Al(ClO4)3 aqueous solution. We demonstrate that the ultrasound-treated graphite offers the improved reversibility of the ClO4- anion (de)intercalation compared with the untreated samples. The ex situ and in situ Raman spectroelectrochemistry and X-ray diffraction analysis of the ultrasound-treated materials shows no change in the interlayer spacing, a mild increase in the stacking order, and a large increase in the amount of defects in the lattice accompanied by a decrease in the lateral crystallite size. The smaller flakes of the ultrasonicated natural graphite facilitate the improved reversibility of the ClO4- anion electrochemical (de)intercalation and a more stable electrochemical performance with a cycle life of over 300 cycles.

Association of Aortic Valve Sclerosis with Angiographic Severity of Coronary Artery Disease in Patients with Acute Coronary Syndrome, Aged ≤65 Years.

Aortic valve sclerosis (AVS) represents a degenerative process that progresses with advancing age. The study was intended to find out the association between aortic valve sclerosis and the severity of CAD in patient's age ≤65 years with acute coronary syndrome. This cross-sectional analytical study was carried out in the department of cardiology, National Institute of Cardiovascular Diseases (NICVD), Dhaka, Bangladesh during a period of October 2017 to September 2018. A total of 140 Acute coronary syndrome (ACS) patients undergoing coronary angiogram during index hospitalization were included in the study. Study patients were divided into two groups on the basis of echocardiographic presence or absence of Aortic valve sclerosis (AVS), with 70 patients in each group. Group I was patients with aortic valve sclerosis and Group II was patients without aortic valve sclerosis. All patients underwent transthoracic echocardiography before they underwent coronary angiography on different days. Severity of CAD was determined by Gensini score and Vessel score. Association of traditional risk factors (smoking habit, hypertension, diabetes mellitus, dyslipidaemia and family history of CAD) with severity of CAD was investigated. Coronary angiography showed that AVS group had a higher positive rate of CAD (82.9% vs. 54.3%, p<0.001) and incidence rate of triple vessel CAD (40% vs. 14.3%, p<0.001) than non-AVS group. Gensini score had higher in AVS group than non AVS group (37.9±27.8 vs. 12.5±14.2; p<0.001). Multivariate analysis showed that AVS (p=0.01) and age (p=0.04) were independent predictors of the presence of significant coronary artery disease. The study concluded that echocardiographically detected AVS is an independent predictor of coronary artery disease severity. There is positive correlation between severity of AVS and severity of CAD in patient's age ≤65 years with ACS.

Association of Diastolic Dysfunction with Angiographic Severity of Coronary Artery Disease in patients with Non-ST Elevation Myocardial Infarction.

In recent years, diastolic dysfunction is an evolving context. Presence of left ventricular diastolic dysfunction (LVDD) indicates a poor prognosis in patients with an ACS and chronic coronary artery diseases. This study evaluated the association of LVDD and angiographic severity of CAD in patients with non-ST elevation myocardial infarction (NSTEMI). This cross-sectional analytical study was carried out in National Institute of Cardiovascular Diseases, Dhaka, Bangladesh, during the period of April 2017 to March 2018. A total of 120 NSTEMI patients undergoing coronary angiogram (CAG) during index hospitalization were included in the study. All patients underwent transthoracic echocardiography before they underwent CAG on different days. Presence (Group I, n=65) and absence of LVDD (Group II, n=55) was established by echocardiography. Severity of CAD was assessed by Vessel score and Leaman score. Association of traditional risk factors (smoking habit, hypertension, diabetes mellitus, dyslipidemia and family history of CAD) with severity of CAD was investigated. Vessel score showed coronary artery obstruction (CAO) was present in 62(95.4%) patients in Group I and 35(63.6%) patients in Group II, single vessel was involved in 17(27.4%) patients while multi vessel in 45(72.6%) patients was found in Group I. On the contrary 27(77.1%) single vessel patients and 8(22.9%) multi vessel patients were found in Group II. Positive Leaman score was significantly higher in Group I, 62(95.4%) than that of Group II, 35(63.6%) which is statistically significant (p<0.001). This study showed a positive correlation between LVDD and CAD severity in terms of vessel score and Leamanscore. This study also demonstrates that the severity of vessel score and Leaman score was higher in the higher grade of diastolic dysfunction. The present study concludes that LVDD is associated with angiographically severe CAD in patients with NSTEMI.

Divergent prognostic effects of pre-existing and treatment-emergent thyroid dysfunction in patients treated with immune checkpoint inhibitors.

BACKGROUND: Thyroid dysfunction is among the most common autoimmune diseases and immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAE). We determined the association between longitudinal thyroid function and clinical outcomes in patients treated with ICI. METHODS: We identified all patients treated with ICI at UT Southwestern Medical Center from January 1, 2011, through December 31, 2020. We defined normal thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels according to institutional reference range. We defined clinical thyroid dysfunction using established criteria incorporating labs and treatment. We determined the association between thyroid function and overall survival (OS) using Kaplan-Meier curves, log-rank tests, and multivariate Cox proportional hazards model. RESULTS: A total of 1781 patients were included in analyses, of whom 381 (21%) had abnormal baseline TSH. Patients with abnormal baseline TSH were more likely to be female, have kidney cancer, and initiate levothyroxine after ICI initiation (all P < 0.001). Patients with abnormal baseline TSH had inferior OS (median 16 vs 27 months; P < 0.001). Among patients with normal baseline TSH, those who had abnormal TSH after ICI initiation had improved OS (median 41 vs 22 months; P < 0.001). In a multivariate Cox model, abnormal baseline TSH was associated with worse OS (HR 1.62; 95% CI, 1.30-2.02; P < 0.001), while initiation of levothyroxine after ICI initiation was associated with improved OS (HR 0.62; 95% CI, 0.44-0.88; P = 0.008). CONCLUSIONS: ICI-induced thyroid dysfunction is associated with improved survival, although abnormal TSH prior to ICI initiation is associated with inferior survival. PRECIS: Thyroid abnormalities occur commonly in the general population and as immunotherapy toxicities. We found that immunotherapy-induced thyroid dysfunction is associated with better survival, but pre-existing thyroid abnormalities convey worse outcomes.

Concentration-dependent Early Antivascular and Antitumor Effects of Itraconazole in Non-Small Cell Lung Cancer.

PURPOSE: Itraconazole has been repurposed as an anticancer therapeutic agent for multiple malignancies. In preclinical models, itraconazole has antiangiogenic properties and inhibits Hedgehog pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients. EXPERIMENTAL DESIGN: Patients with non-small cell lung cancer (NSCLC) who had planned for surgical resection were administered with itraconazole 300 mg orally twice daily for 10-14 days. Patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic and pharmacodynamic analyses. Tissues from pretreatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyitraconazole concentration, and vascular and Hedgehog pathway biomarkers. RESULTS: Thirteen patients were enrolled in this study. Itraconazole was well-tolerated. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole demonstrated a 6-fold difference across patients. Tumor itraconazole concentrations trended with and exceeded those of plasma. Greater itraconazole levels were significantly and meaningfully associated with reduction in tumor volume (Spearman correlation, -0.71; P = 0.05) and tumor perfusion (Ktrans; Spearman correlation, -0.71; P = 0.01), decrease in the proangiogenic cytokines IL1b (Spearman correlation, -0.73; P = 0.01) and GM-CSF (Spearman correlation, -1.00; P < 0.001), and reduction in tumor microvessel density (Spearman correlation, -0.69; P = 0.03). Itraconazole-treated tumors also demonstrated distinct metabolic profiles. Itraconazole treatment did not alter transcription of GLI1 and PTCH1 mRNA. Patient size, renal function, and hepatic function did not predict itraconazole concentrations. CONCLUSIONS: Itraconazole demonstrates concentration-dependent early antivascular, metabolic, and antitumor effects in patients with NSCLC. As the number of fixed dose cancer therapies increases, attention to interpatient pharmacokinetics and pharmacodynamics differences may be warranted.

XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition.

Persistent R-loops (RNA-DNA hybrids with a displaced single-stranded DNA) create DNA damage and lead to genomic instability. The 5'-3'-exoribonuclease 2 (XRN2) degrades RNA to resolve R-loops and promotes transcription termination. Previously, XRN2 was implicated in DNA double strand break (DSB) repair and in resolving replication stress. Here, using tandem affinity purification-mass spectrometry, bioinformatics, and biochemical approaches, we found that XRN2 associates with proteins involved in DNA repair/replication (Ku70-Ku80, DNA-PKcs, PARP1, MCM2-7, PCNA, RPA1) and RNA metabolism (RNA helicases, PRP19, p54(nrb), splicing factors). Novel major pathways linked to XRN2 include cell cycle control of chromosomal replication and DSB repair by non-homologous end joining. Investigating the biological implications of these interactions led us to discover that XRN2 depletion compromised cell survival after additional knockdown of specific DNA repair proteins, including PARP1. XRN2-deficient cells also showed enhanced PARP1 activity. Consistent with concurrent depletion of XRN2 and PARP1 promoting cell death, XRN2-deficient fibroblast and lung cancer cells also demonstrated sensitivity to PARP1 inhibition. XRN2 alterations (mutations, copy number/expression changes) are frequent in cancers. Thus, PARP1 inhibition could target cancers exhibiting XRN2 functional loss. Collectively, our data suggest XRN2's association with novel protein partners and unravel synthetic lethality between XRN2 depletion and PARP1 inhibition.

Statin Intolerance, Anti-HMGCR Antibodies, and Immune Checkpoint Inhibitor-Associated Myositis: A "Two-Hit" Autoimmune Toxicity or Clinical Predisposition?

Immune-related adverse events induced by immune checkpoint inhibitor (ICI) therapy may affect diverse organ systems, including skeletal and cardiac muscle. ICI-associated myositis may result in substantial morbidity and occasional mortality. We present a case of a patient with advanced non-small cell lung cancer who developed grade 4 myositis with concurrent myocarditis early after initiation of anti-programmed death ligand 1 therapy (durvalumab). Autoantibody analysis revealed marked increases in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody levels that preceded clinical toxicity, and further increased during toxicity. Notably, the patient had a history of intolerable statin myopathy, which had resolved clinically after statin discontinuation and prior to ICI initiation. This case demonstrates a potential association between statin exposure, autoantibodies, and ICI-associated myositis.

Late-Onset Immunotherapy Toxicity and Delayed Autoantibody Changes: Checkpoint Inhibitor-Induced Raynaud's-Like Phenomenon.

Immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAEs) may affect almost any organ system and occur at any point during therapy. Autoantibody analysis may provide insight into the mechanism, nature, and timing of these events. We report a case of ICI-induced late-onset Raynaud's-like phenomenon in a patient receiving combination immunotherapy. A 53-year-old woman with advanced non-small lung cancer received combination anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed death 1 ICI therapy. She developed early (hypophysitis at 4 months) and late (Raynaud's at >20 months) irAEs. Longitudinal assessment of 124 autoantibodies was correlated with toxicity. Although autoantibody levels were generally stable for the first 18 months of therapy, shortly before the development of Raynaud's, a marked increase in multiple autoantibodies was observed. This case highlights the potential for delayed autoimmune toxicities and provides potential biologic insights into the dynamic nature of these events. KEY POINTS: A patient treated with dual anti-PD1 and anti-CTLA4 therapy developed Raynaud's-like signs and symptoms more than 18 months after starting therapy. In this case, autoantibody changes became apparent shortly before onset of clinical toxicity. This case highlights the potential for late-onset immune-related adverse events checkpoint inhibitors, requiring continuous clinical vigilance. The optimal duration of checkpoint inhibitor therapy in patients with profound and prolonged responses remains unclear.

Enhanced and Faster Potassium Storage in Graphene with Respect to Graphite: A Comparative Study with Lithium Storage.

The mechanisms, extent, and rate of K-storage in graphenic and graphitic carbons, as direct comparisons with Li-storage in the same structures/materials, in terms of the effects of dimensional scale and presence of surface and exposed edge sites have been brought to the fore via DFT-based simulations, duly complemented and supplemented by experimental studies. The simulation indicates feasibilities toward K-storage on single-layer graphene (SLG) at a concentration greater than that in graphite ( i. e., beyond KC8), the formation of more than one layer of K on SLG, and K-storage on both the surfaces of SLG, unlike that for Li-storage. Simulations done with graphene nanoribbons (GNRs) indicate that K can get hosted on the graphene surfaces and at the exposed "stepped" edges, in addition to the "classical" K-intercalation in-between the constituent graphene layers. Accordingly, the computation studies indicate considerably enhanced K-storage "specific capacity" of GNR, as compared to bulk graphite, with the capacity decreasing with the increase in number of graphene layers. Electrochemical potassiation/depotassiation of well-ordered fairly pristine few layers graphene films (FLG; ∼6-7 layers) confirms the simultaneous occurrences of bulk ( i. e., K-intercalation) and surface storage of K, resulting in reversible K-storage capacity being greater than that of thicker bulk graphite films by a factor of ∼2.5. This is in agreement with the predictions from DFT. However, this increment is less compared to that for Li-storage, again in accordance with the DFT results. Our measurements indicate lower diffusivity of K, as compared to Li, in the same graphitic structure by an order of magnitude. Accordingly, the rate capability of K-storage in graphite has been found to be considerably inferior to Li-storage, which renders the reduction in dimensional scale even more important in the case of K-storage, as observed here with FLG.

Immune dysregulation in cancer patients developing immune-related adverse events.

BACKGROUND: Up to 40% of cancer patients on immune checkpoint inhibitors develop clinically significant immune-related adverse events (irAEs). The role of host immune status and function in predisposing patients to the development of irAEs remains unknown. METHODS: Sera from 65 patients receiving immune checkpoint inhibitors and 13 healthy controls were evaluated for 40 cytokines at pre-treatment, after 2-3 weeks and after 6 weeks and analysed for correlation with the development of irAEs. RESULTS: Of the 65 cancer patients enrolled, 55% were women; the mean age was 65 years and 98% received anti-PD1/PDL1 therapy. irAEs occurred in 35% of cases. Among healthy controls, cytokine levels were stable over time and lower than those in cancer patients at baseline. Significant increases in CXCL9, CXCL10, CXCL11 and CXCL13 occurred 2 weeks post treatment, and in CXCL9, CXCL10, CXCL11, CXCL13, IL-10 and CCL26 at 6 weeks post treatment. Patients who developed irAEs had lower levels of CXCL9, CXCL10, CXCL11 and CXCL19 at baseline and exhibited greater increases in CXCL9 and CXCL10 levels at post treatment compared to patients without irAEs. CONCLUSIONS: Patients who developed irAEs have lower baseline levels and greater post-treatment increases in multiple cytokine levels, suggesting that underlying immune dysregulation may be associated with heightened risk for irAEs.

Kub5-Hera RPRD1B Deficiency Promotes "BRCAness" and Vulnerability to PARP Inhibition in BRCA-proficient Breast Cancers.

PURPOSE: Identification of novel strategies to expand the use of PARP inhibitors beyond BRCA deficiency is of great interest in personalized medicine. Here, we investigated the unannotated role of Kub5-HeraRPRD1B (K-H) in homologous recombination (HR) repair and its potential clinical significance in targeted cancer therapy. EXPERIMENTAL DESIGN: Functional characterization of K-H alterations on HR repair of double-strand breaks (DSB) were assessed by targeted gene silencing, plasmid reporter assays, immunofluorescence, and Western blots. Cell survival with PARP inhibitors was evaluated through colony-forming assays and statistically analyzed for correlation with K-H expression in various BRCA1/2 nonmutated breast cancers. Gene expression microarray/qPCR analyses, chromatin immunoprecipitation, and rescue experiments were used to investigate molecular mechanisms of action. RESULTS: K-H expression loss correlates with rucaparib LD50 values in a panel of BRCA1/2 nonmutated breast cancers. Mechanistically, K-H depletion promotes BRCAness, where extensive upregulation of PARP1 activity was required for the survival of breast cancer cells. PARP inhibition in these cells led to synthetic lethality that was rescued by wild-type K-H reexpression, but not by a mutant K-H (p.R106A) that weakly binds RNAPII. K-H mediates HR by facilitating recruitment of RNAPII to the promoter region of a critical DNA damage response and repair effector, cyclin-dependent kinase 1 (CDK1). CONCLUSIONS: Cancer cells with low K-H expression may have exploitable BRCAness properties that greatly expand the use of PARP inhibitors beyond BRCA mutations. Our results suggest that aberrant K-H alterations may have vital translational implications in cellular responses/survival to DNA damage, carcinogenesis, and personalized medicine.