Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome.

Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies.

Dark Matter Induced Power in Quantum Devices.

We point out that power measurements of single quasiparticle devices open a new avenue to detect dark matter (DM). The threshold of these devices is set by the Cooper pair binding energy, and is therefore so low that they can detect DM as light as about an MeV incoming from the Galactic halo, as well as the low-velocity thermalized DM component potentially present in the Earth. Using existing power measurements with these new devices, as well as power measurements with SuperCDMS-CPD, we set new constraints on the spin-independent DM scattering cross section for DM masses from about 10 MeV to 10 GeV. We outline future directions to improve sensitivity to both halo DM and a thermalized DM population in the Earth using power deposition in quantum devices.

Update on cancer predisposition syndromes and surveillance guidelines for childhood brain tumors.

Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease aetiology increases. Some children with brain tumors may present with non-malignant phenotypic features of specific syndromes (e.g. nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch repair deficiency), while others may present with a strong family history of cancer (e.g. Li-Fraumeni syndrome), or with a rare tumor commonly found in the context of germline predisposition (e.g. rhabdoid tumor predisposition syndrome). Approximately 50% of patients with a brain tumor may be the first in a family identified to have a predisposition. The past decade has witnessed a rapid expansion in our molecular understanding of CNS tumors. A significant proportion of CNS tumors are now well characterized and known to harbor specific genetic changes that can be found in the germline. Additional novel predisposition syndromes are also being described. Identification of these germline syndromes in individual patients has not only enabled cascade testing of family members and early tumor surveillance but increasingly has also impacted cancer management in those patients. Therefore, the AACR Cancer Predisposition Working Group chose to highlight these advances in CNS tumor predisposition and summarize and/or generate surveillance recommendations for established and more recently emerging pediatric brain tumor predisposition syndromes.

Effects of PNA Sequence and Target Site Selection on Function of a 4.5S Non-Coding RNA.

Peptide nucleic acid (PNA) based antisense strategy is a promising therapeutic approach to specifically inhibit target gene expression. However, unlike protein coding genes, identification of an ideal PNA binding site for non-coding RNA is not straightforward. Here, we compare the inhibitory activities of PNA molecules that bind a non-coding 4.5S RNA called SRP RNA, a key component of the bacterial signal recognition particle (SRP). A 9-mer PNA (PNA9) complementary to the tetraloop region of the RNA was more potent in inhibiting its interaction with the SRP protein, compared to an 8-mer PNA (PNA8) targeting a stem-loop. PNA9, which contained a homo-pyrimidine sequence could form a triplex with the complementary stretch of RNA in vitro as confirmed using a fluorescent derivative of PNA9 (F-PNA13). The RNA-PNA complex formation resulted in inhibition of SRP function with PNA9 and F-PNA13, but not PNA8 highlighting the importance of target site selection. Surprisingly, F-PNA13 which was more potent in inhibiting SRP function in vitro, showed weaker antibacterial activity compared to PNA9 likely due to poor cell penetration of the longer PNA. Our results underscore the importance of suitable target site selection and optimum PNA length to develop better antisense molecules against non-coding RNA.

A fluorescent MOF and its synthesized MOF@cotton composite: Ratiometric sensing of vitamin B2 and antibiotic drug molecule.

Here, we demonstrated the synthesis of a zinc based luminescent MOF, 1 (NDC = 2,6- naphthalenedicarboxylate) for the ratiometric detection of biomarker riboflavin (RBF; vitamin B2) in water dispersed medium. Further, this MOF detected two other antibiotic drug molecules, nitrofurantoin (NFT) and nitrofurazone (NZF). The detection of these analytes is very quick (∼seconds), and the limit of detection (LOD) for RBF, NZF and NFT are calculated as 16.58 ppm, 47.63 ppb and 56.96 ppb, respectively. The detection of these analytes was also comprehended by solid, solution, cost-effective paper strip method i.e., triphasic identification capabilities. The sensor is reusable without losing its detection efficacy. The sensor further showed the recognition abilities of these antibiotics in real field samples (river water, urine and tablet) and RBF in vitamin B2 pills and food samples (milk and cold drinks). The sensing merit of 1 urged us to fabricate of 1@cotton fabric composite, which exhibited the colorimetric detection of these analytes. In-depth experimental analysis suggested that the occurrence of photo-induced electron transfer (PET), fluorescence resonance energy transfer (FRET), and the inner filter effect (IFE) are the possible sensing mechanisms for the recognition of the antibiotics drug. The FRET mechanism is responsible for the recognition of RBF. The sensing mechanism is further supported by the theoretical analysis and the excited lifetime measurement.

Spatiotemporal variations, sources, pollution status and health risk assessment of dissolved trace elements in a major Arabian Sea draining river: insights from multivariate statistical and machine learning approaches.

River Mahi drains through semi-arid regions (Western India) and is a major Arabian Sea draining river. As the principal surface water source, its water quality is important to the regional population. Therefore, the river water was sampled extensively (n = 64, 16 locations, 4 seasons and 2 years) and analyzed for 11 trace elements (TEs; Sr, V, Cu, Ni, Zn, Cd, Ba, Cr, Mn, Fe, and Co). Machine learning (ML) and multivariate statistical analysis (MVSA) were applied to investigate their possible sources, spatial-temporal-annual variations, evaluate multiple water quality parameters [heavy metal pollution index (HPI), heavy metal evaluation index (HEI)], and health indices [hazard quotient (HQ), and hazard index (THI)] associated with TEs. TE levels were higher than their corresponding world average values in 100% (Sr, V and Zn), 78%(Cu), 41%(Ni), 27%(Cr), 9%(Cd), 8%(Ba), 8%(Co), 6%(Fe), and 0%(Mn), of the samples. Three principal components (PCs) accounted for 74.5% of the TE variance: PC-1 (Fe, Co, Mn and Cu) and PC-2 (Sr and Ba) are contributed from geogenic sources, while PC-3 (Cr, Ni and Zn) are derived from geogenic and anthropogenic sources. HPI, HEI, HQ and THI all indicate that water quality is good for domestic purposes and poses little hazard. ML identified Random forest as the most suitable model for predicting HEI class (accuracy: 92%, recall: 92% and precision: 94%). Even with a limited dataset, the study underscores the potential application of ML to predictive classification modeling.

A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis is often hampered by the identification of mismatch repair (MMR) variants of unknown significance and difficulties in PMS2 analysis, the most frequently mutated gene in CMMRD. We present the validation of a robust functional tool for CMMRD diagnosis and the characterization of microsatellite instability (MSI) patterns in blood and tumors. METHODS: The highly sensitive assessment of MSI (hs-MSI) was tested on a blinded cohort of 66 blood samples and 24 CMMRD tumor samples. Hs-MSI scores were compared with low-pass genomic instability scores (LOGIC/MMRDness). The correlation of hs-MSI scores in blood with age of cancer onset and the distribution of insertion-deletion (indel) variants in microsatellites were analyzed in a series of 169 individuals (n = 68 CMMRD, n = 124 non-CMMRD). RESULTS: Hs-MSI achieved high accuracy in the identification of CMMRD in blood (sensitivity 98.5% and specificity 100%) and detected MSI in CMMRD-associated tumors. Hs-MSI had a strong positive correlation with whole low-pass genomic instability LOGIC scores (r = 0.89, P = 2.2e-15 in blood and r = 0.82, P = 7e-3 in tumors). Indel distribution identified PMS2 pathogenic variant (PV) carriers from other biallelic MMR gene PV carriers with an accuracy of 0.997. Higher hs-MSI scores correlated with younger age at diagnosis of the first tumor (r = -0.43, P = 0.011). CONCLUSIONS: Our study confirms the accuracy of the hs-MSI assay as ancillary testing for CMMRD diagnosis, which can also characterize MSI patterns in CMMRD-associated cancers. Hs-MSI is a powerful tool to pinpoint PMS2 as the affected germline gene and thus potentially personalize cancer risk.

Actively Driven Light-Addressable Sensor/Actuator System for Automated pH Control for the Integration in Lab-On-A-Chip (LoC) Platforms.

The miniaturization of microfluidic systems usually comes at the cost of more difficult integration of sensors and actuators inside the channel. As an alternative, this work demonstrates the embedding of semiconductor-based sensor and actuator technologies that can be spatially and temporally controlled from outside the channel using light. The first element is a light-addressable potentiometric sensor, consisting of an Al/Si/SiO2/Si3N4 structure, that can measure pH changes at the Si3N4/electrolyte interface. The pH value is a crucial factor in biological and chemical systems, and besides measuring, it is often important to bring the system out of equilibrium or to adjust and control precisely the surrounding medium. This can be done photoelectrocatalytically by utilizing light-addressable electrodes. These consist of a glass/SnO2:F/TiO2 structure, whereby direct charge transfer between the TiO2 and the electrolyte leads to a pH change upon irradiation. To complement the advantages of both, we integrated a light-addressable sensor with a pH sensitivity of 41.5 mV·pH-1 and a light-addressable electrode into a microfluidic setup. Here, we demonstrated a simultaneous operation with the ability to generate and record pH gradients inside a channel under static and dynamic flow conditions. The results show that dependent on the light-addressable electrode (LAE)-illumination conditions, pH changes up to ΔpH of 2.75 and of 3.52 under static and dynamic conditions, respectively, were spatially monitored by the light-addressable potentiometric sensor. After flushing with fresh buffer solution, the pH returned to its initial value. Depending on the LAE illumination, pH gradients with a maximum pH change of ΔpH of 1.42 were tailored perpendicular to the flow direction. In a final experiment, synchronous LAE illumination led to a stepwise increase in the pH inside the channel.

Metastatic Neuroblastoma in the Testis: Report of a Case with Review of Literature.

Neuroblastoma is the most common extracranial malignant solid tumor in childhood. Neuroblastoma is known to metastasize in certain niche areas such as the bone, bone marrow, liver, and skin. Testicular metastasis of neuroblastoma is uncommon, and only a few cases have been reported. In this communique, we describe an infant with neuroblastoma presenting with testicular metastasis. Testicular metastasis of neuroblastoma, although uncommon, should be considered a differential of testicular masses in children.

Spatial and Temporal Variations in Richness, Diversity and Abundance of Floral Visitors of Curry Plants (Bergera koenigii L.): Insights on Plant-Pollinator Interactions.

The reproductive success of flowering plants relates to flower-visitor communities and plant-pollinator interactions. These traits are species- and region-specific and vary across regions, pollinator groups, and plant species. However, little literature exists on the spatiotemporal variation in visitor activity, especially in India. Here, we aimed to depict the spatial and temporal variation in visitor activity on the curry plants (Bergera koenigii). Data were collected at different daytime slots from three vegetation zones (confirmed by field surveys and normalized difference vegetation index values in remote sensing)-dense, medium-density, and low-density vegetation in West Bengal, India. The visitors' richness, diversity, and abundance were higher in the area with dense vegetation. Considering daytime patterns, higher values for these parameters were obtained during 10.00-14.00 h. For most visitors, the flower handling time was shorter, and the visitation rate was higher in dense vegetation areas (at 10.00-14.00 h) than in medium- and low-density vegetation areas. The proportions of different foraging categories varied over time. Vital pollinators were Apis cerana, Apis dorsata, Appias libythea, Halictus acrocephalus, Nomia iridescens, and Tetragonula iridipennis. However, the effectiveness of pollinators remained region-specific. Therefore, it can be concluded that floral visitors' richness, diversity, abundance, and plant-visitor interactions varied spatially with their surrounding vegetation types and also changed daytime-wise.

Brain-state mediated modulation of inter-laminar dependencies in visual cortex.

Spatial attention is a quintessential example of adaptive information processing in the brain and is critical for recognizing behaviorally relevant objects in a cluttered environment. Object recognition is mediated by neural encoding along the ventral visual hierarchy. How the deployment of spatial attention aids these hierarchical computations is unclear. Prior studies point to two distinct mechanisms: an improvement in the efficacy of information directed from one encoding stage to another, and/or a suppression of shared information within encoding stages. To test these proposals, it is crucial to estimate the attentional modulation of unique information flow across and shared information within the encoding stages of the visual hierarchy. We investigated this in the multi-stage laminar network of visual area V4, an area strongly modulated by attention. Using network-based dependency estimation from multivariate data, we quantified the modulation of inter-layer information flow during a change detection task and found that deployment of attention indeed strengthened unique dependencies between the input and superficial layers. Using the partial information decomposition framework, we estimated the modulation of shared dependencies and found that they are reduced specifically in the putative excitatory subpopulations within a layer. Surprisingly, we found a strengthening of unique dependencies within the laminar populations, a finding not previously predicted. Crucially, these modulation patterns were also observed during successful behavioral outcomes (hits) that are thought to be mediated by endogenous brain state fluctuations, and not by experimentally imposed attentive states. Finally, phases of endogenous fluctuations that were optimal for 'hits' were associated with reduced neural excitability. A reduction in neural excitability, potentially mediated by diminished shared inputs, suggests a novel mechanism for enhancing unique information transmission during optimal states. By decomposing the modulation of multivariate information, and combined with prior theoretical work, our results suggest common computations of optimal sensory states that are attained by either task demands or endogenous fluctuations.

Proton Therapy Mediates Dose Reductions to Brain Structures Associated With Cognition in Children With Medulloblastoma.

PURPOSE: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy. METHODS AND MATERIALS: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores. RESULTS: The mean dose and dose to 40% of the brain (D40) were 2.7 and 4.1 Gy less among proton-treated patients compared with photon-treated patients (P = .03 and .007, respectively). Mean doses to the left and right hippocampi were 11.2 Gy lower among proton-treated patients (P < .001 for both). Mean doses to the left and right temporal lobes were 6.9 and 7.1 Gy lower with proton treatment, respectively (P < .001 for both). Models of cognition found statistically significant associations between higher mean brain dose and reduced verbal comprehension, increased right temporal lobe D40 with reduced perceptual reasoning, and greater left temporal mean dose with reduced working memory. Higher brain D40 was associated with reduced processing speed and global IQ scores. CONCLUSIONS: Proton therapy reduces doses to normal brain structures compared with photon treatment. This leads to reduced cognitive decline after radiation therapy across multiple intellectual endpoints. Proton therapy should be offered to children receiving radiation for medulloblastoma.

A Gate-Tunable Ambipolar Quantum Phase Transition in a Topological Excitonic Insulator.

Coulomb interactions among electrons and holes in 2D semimetals with overlapping valence and conduction bands can give rise to a correlated insulating ground state via exciton formation and condensation. One candidate material in which such excitonic state uniquely combines with non-trivial band topology are atomic monolayers of tungsten ditelluride (WTe2 ), in which a 2D topological excitonic insulator (2D TEI) forms. However, the detailed mechanism of the 2D bulk gap formation in WTe2 , in particular with regard to the role of Coulomb interactions, has remained a subject of ongoing debate. Here, it shows that WTe2 is susceptible to a gate-tunable quantum phase transition, evident from an abrupt collapse of its 2D bulk energy gap upon ambipolar field-effect doping. Such gate tunability of a 2D TEI, into either n- and p-type semimetals, promises novel handles of control over non-trivial 2D superconductivity with excitonic pairing.

Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium.

Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology. SIGNIFICANCE: Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201.

Assessment of Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Carcinoma Using Image-Guided Clip Placement.

Background The present study aims to evaluate the response of locally advanced breast carcinoma (LABC) to neoadjuvant chemotherapy (NACT) using image-guided clip placement based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Methods Thirty-four patients with LABC were included in the study. Consent for three-dimensional titanium clip placement (400/300/200 mm Liga clips) under local anesthesia with USG guidance was obtained. Serial sonographic/X-ray evaluations of tumor bed size were conducted before every cycle of NACT. All data were recorded in millimeters of concentric tumor regression/non-regression. Tumor regression in a concentric or Swiss cheese pattern and non-responders were evaluated. Assessment of the response to NACT was performed using RECIST criteria, dividing it into four categories. Tumor response was confirmed with computerized tomography (CT) conducted before and after the completion of NACT. Patients underwent surgical management, mostly modified radical mastectomy (MRM), as they had locally advanced breast carcinoma. Following MRM, the clips in the specimen guided the original site of the tumor for histopathological evaluation and response to chemotherapy. Results Tumor response was classified into four types: complete response (CR), partial response (PR), progressive disease (PD), and stable disease. RECIST 1.1 criteria were elaborated and defined. Data for all patients were entered into an Excel sheet (Microsoft Corporation, Redmond, Washington) to prepare a master chart, and the following observations were made and analyzed using SPSS software. The duration of chemotherapy for the study population ranged from 32 to 206 days, with a mean (±SD) of 111.82 (± 52.64) days and a median (IQR) of 81 (63, 158) days. The mean period between clip insertion and completion of NACT was 111.82 days. The baseline sum diameters and post-NACT diameters of the tumors were 70.50 (±13.60) mm before NACT and 17.75 (±17.20) mm after NACT. Hence, the mean size of the lump was statistically significantly lower after NACT, with a mean difference of 52.75 (p<0.05). The mean rate of reduction in tumor diameter was found to be 74.32% (±23.44%) based on RECIST 1.1 criteria. Pathological response was observed in all patients except for 8.8% of the patients. Clinical complete response was seen in 35.29% of patients, and partial response was observed in 52.92% of the patients based on RECIST 1.1 criteria. The study thus demonstrates the effectiveness of NACT in LABC, with a mean reduction in tumor diameter of 74.32%, assessed with the help of RECIST 1.1 criteria. Conclusion NACT for patients with LABC has shown a significant reduction in tumor size. NACT should be the initial mode of management for patients with LABC. RECIST 1.1 criteria are effective and can be used to assess tumor response to NACT. This has aided in the stratification of the response of NACT for further management through systemic therapy (adjuvant chemotherapy) after the surgical excision of the tumor.

Amyloidogenic propensity of self-assembling peptides and their adjuvant potential for use as DNA vaccines.

De novo designed peptides that self-assemble into cross-ß rich fibrillar biomaterials have been pursued as an innovative platform for the development of adjuvant- and inflammation-free vaccines. However, they share structural and morphological properties similar to amyloid species implicated in neurodegenerative diseases, which has been a long-standing concern for their successful translation. Here, we comprehensively characterize the amyloidogenic character of the amphipathic self-assembling cross-ß peptide KFE8, compared to pathological amyloid and amyloid-like proteins α-synuclein (α-syn) and TDP-43. Further, we developed plasmid-based DNA vaccines with the KFE8 backbone serving as a scaffold for delivery of a GFP model antigen. We find that expression of tandem repeats of KFE8 is non-toxic and efficiently cleared by autophagy. We also demonstrate that preformed KFE8 fibrils do not cross-seed amyloid formation of α-syn in mammalian cells compared to α-syn preformed fibrils. In mice, vaccination with plasmids encoding the KFE32-GFP fusion protein elicited robust immune responses, inducing production of significantly higher levels of anti-GFP antibodies compared to soluble GFP. Antigen-specific CD8+T cells were also detected in the spleens of vaccinated mice and cytokine profiles from antigen recall assays indicate a balanced Th1/Th2 response. These findings illustrate that cross-ß-rich peptide nanofibers have distinct physicochemical properties from those of pathological amyloidogenic proteins, and are an attractive platform for the development of DNA vaccines with self-adjuvanting properties and improved safety profiles. STATEMENT OF SIGNIFICANCE: Biomaterials comprised of self-assembling peptides hold great promise for the development of new vaccines that do not require use of adjuvants. However, these materials have safety concerns, as they self-assemble into cross-ß rich fibrils that are structurally similar to amyloid species implicated in disease. Here, we comprehensively study the properties of these biomaterials. We demonstrate that they have distinct properties from pathological proteins. They are non-toxic and do not trigger amyloidogenesis. Vaccination of these materials in mice elicited a robust immune response. Most excitingly, our work suggests that this platform could be used to develop DNA-based vaccines, which have few storage requirements. Further, due to their genetic encoding, longer sequences can be generated and the vaccines will be amenable to modification.

Investigation of Photoelectrocatalytic and Magnetic Properties of Sr2YbRu1-xTaxO6 (x = 0, 0.25, 0.5, 0.75, and 1).

We report the effect of substitution of Ru by Ta in Sr2YbRuO6 on its magnetic and photoelectrocatalytic properties. The powder X-ray diffraction data, was satisfactorily refined in the monoclinic space group, P21/n. The DC magnetization studies indicated that Sr2YbRuO6 shows antiferromagnetic interaction through Yb-O-Ru orbital ordering, with the highest Weiss temperature, among Sr2YbRu1-xTaxO6 (x = 0, 0.25, 0.5, and 0.75) which have values of -148, -125, -118, and -102 K, respectively. The difference in observed and theoretical magnetic moments was found to increase as x increases. It was also observed that with the increase of Ta concentration in Sr2YbRu1-xTaxO6, the band gap increased almost linearly, from 1.78(1) eV (x = 0) to 2.08(1) (x = 0.75), and thereafter a sharp increase 2.65(1) eV (x = 1) was observed, with the lowering of energy level of valence band, along with disruption in orbital ordering as x increases. The photoelectrocatalytic oxygen evolution reaction (OER) studies carried out on the series yield a maximum photocurrent density of 17 µA/cm2 and photoresponse current of 5.5 µA/cm2 at 0.8 V at an onset potential at 0.29 V vs Ag/AgCl for Sr2YbRuO6. The XPS analysis showed Ta and Ru to be in +5/+4 oxidation states, with the highest concentration of Ru4+ ion observed for Sr2YbRuO6. The presence of oxygen vacancies was confirmed by XPS as well as EPR studies.

Efficacy of Nivolumab in Pediatric Cancers with High Mutation Burden and Mismatch Repair Deficiency.

PURPOSE: Checkpoint inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for refractory nonhematologic cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch repair deficiency (MMRD). PATIENTS AND METHODS: Twenty patients were screened, and 10 were ultimately included in the response cohort of whom nine had TMB >10 mut/Mb (three initially eligible based on MMRD) and one patient had TMB between 5 and 10 mut/Mb. RESULTS: Delayed immune responses contributed to best overall response of 50%, improving on initial objective responses (20%) and leading to 2-year overall survival (OS) of 50% [95% confidence interval (CI), 27-93]. Four children, including three with refractory malignant gliomas are in complete remission at a median follow-up of 37 months (range, 32.4-60), culminating in 2-year OS of 43% (95% CI, 18.2-100). Biomarker analyses confirmed benefit in children with germline MMRD, microsatellite instability, higher activated and lower regulatory circulating T cells. Stochastic mutation accumulation driven by underlying germline MMRD impacted the tumor microenvironment, contributing to delayed responses. No benefit was observed in the single patient with an MMR-proficient tumor and TMB 7.4 mut/Mb. CONCLUSIONS: Nivolumab resulted in durable responses and prolonged survival for the first time in a pediatric trial of refractory hypermutated cancers including malignant gliomas. Novel biomarkers identified here need to be translated rapidly to clinical care to identify children who can benefit from checkpoint inhibitors, including upfront management of cancer. See related commentary by Mardis, p. 4701.

Fishbone-Induced Appendicular Perforation: A Rare Case Report of Amyand's Hernia.

Amyand's hernia is a rare type of hernia where the appendix is found to be the content of the inguinal hernial sac. It is most often diagnosed intraoperatively wherein the appendix may be found healthy, incarcerated, inflamed, or perforated. Claudius Amyand performed a successful appendectomy on a patient with an appendix noted in the inguinal canal and this condition was hence named after him. The incidence of Amyand's hernia is rare in inguinal hernia patients. There are no defined guidelines for the management of Amyand's hernia but adequate resuscitation followed by immediate appendectomy is widely followed. Here is a case report of a 60-year-old male presenting to the Emergency Department with an irreducible right-side inguinal hernia with features of small bowel obstruction. On exploration, Amyand's hernia was identified with appendicular tip perforation due to an impacted fishbone with pyoperitoneum. Appendectomy was done through midline laparotomy with impacted fishbone removal from the hernial sac with tissue repair of the hernia. There are as such no reported cases of fishbone-induced appendicular perforation in an Amyand's hernia in the available literature. After the exploration, we found the management of the case challenging regarding the closure of the hernia.