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Supporting information include 3 tables and 3 figures. Table 1 describes the Patients characteristics from which primary cell lines were established. Table 2 the characteristics of ovarian tumor samples from which RNA was extracted. Table 3 the characterization of particle formulations Supplementary figure 1 shows the DNA release in vitro in culture medium. The Supplementary figure 2 the ovarian tumors' uptake of c-CPE-NP in vivo. The Supplementary figure 3 shows the survival curves of the tumor bearing mice treated with vehicle, c-CPE-NP encapsulating the empty plasmid or the p16 DTA c-CPE-NP.

Exposure of all nine cell lines to scalar concentrations of ADC for a total of 6 days. IC50 dose response curves of SYD985, T-DM1 and ADC isotype control in all 9 primary USC cell lines with differential HER2 expression tested in vitro (i.e., three with HER2 3+ expression, two with HER2 2+ expression and four with HER2 1+ expression) at 6 days (ie, 144 hrs).

Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer. Up to 35% of USC may overexpress the HER2/neu oncogene at strong (i.e., 3+) levels by IHC while an additional 40% to 50% express HER2/neu at moderate (2+) or low (1+) levels. We investigated the efficacy of SYD985, (Synthon Biopharmaceuticals), a novel HER2-targeting antibody–drug conjugate (ADC) composed of the mAb trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin) in USC. We also compared the antitumor activity of SYD985 in head-to-head experiments to trastuzumab emtansine (T-DM1), a FDA-approved ADC, against multiple primary USC cell lines expressing different levels of HER2/neu in in vitro and in vivo experiments. Using antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing assays as well as propidium iodide–based flow cytometry assays and multiple in vivo USC mouse xenograft models, we demonstrate for the first time that SYD985 is a novel ADC with activity against USC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is 10- to 70-fold more potent than T-DM1 in comparative experiments and, unlike T-DM1, it is active against USC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in patients harboring chemotherapy-resistant USC with low, moderate, and high HER2 expression are warranted. Mol Cancer Ther; 15(8); 1900–9. ©2016 AACR.

Graph showing IC50 values for USPC-ARK-1 cell line after 72 hrs exposure to increasing concentration of neratinib.

Cathepsin B expression. Expression of CTSB vs GAPDH in the primary USC cell lines used for in in vitro validation experiments.

HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC) and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib, and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA-mutated and PIK3CA wild-type HER2/neu–amplified USC cell lines. Cell viability and cell-cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC xenografts. We found both single-agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long-lasting growth inhibition in both USC xenografts when compared with single-agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0–G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single-agent–treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA and pan-ErbB inhibitor–resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild-type PIK3CA resistant to chemotherapy. Mol Cancer Ther; 14(11); 2519–26. ©2015 AACR.

Exposure of all nine cell lines to scalar concentrations of ADC for a total of 3 days. IC50 dose response curves of SYD985, T-DM1 and ADC isotype control in all 9 primary USC cell lines with differential HER2 expression tested in vitro (i.e., three with HER2 3+ expression, two with HER2 2+ expression and four with HER2 1+ expression) at 3 days.

Interpretation of mercury (Hg) geochemistry in environmental systems remains a challenge. This is largely associated with the inability to identify specific Hg transformation processes and species using established analytical methods in Hg geochemistry (total Hg and Hg speciation). In this study, we demonstrate the improved Hg geochemical interpretation, particularly related to process tracing, that can be achieved when Hg stable isotope analyses are complemented by a suite of more established methods and applied to both solid- (soil) and liquid-phases (groundwater) across two Hg

Architectural proteins alter the shape of DNA. Some distort the double helix by introducing sharp kinks. This can serve to relieve strain in tightly-bent DNA structures. Here, we design and test artificial architectural proteins based on a sequence-specific Transcription Activator-like Effector (TALE) protein, either alone or fused to a eukaryotic high mobility group B (HMGB) DNA-bending domain. We hypothesized that TALE protein binding would stiffen DNA to bending and twisting, acting as an architectural protein that antagonizes the formation of small DNA loops. In contrast, fusion to an HMGB domain was hypothesized to generate a targeted DNA-bending architectural protein that facilitates DNA looping. We provide evidence from Escherichia coli Lac repressor gene regulatory loops supporting these hypotheses in living bacteria. Both data fitting to a thermodynamic DNA looping model and sophisticated molecular modeling support the interpretation of these results. We find that TALE protein binding inhibits looping by stiffening DNA to bending and twisting, while the Nhp6A domain enhances looping by bending DNA without introducing twisting flexibility. Our work illustrates artificial approaches to sculpt DNA geometry with functional consequences. Similar approaches may be applicable to tune the stability of small DNA loops in eukaryotes., Graphical Abstract Graphical AbstractThe stability of Lac repressor loops in E. coli is tuned by designed artificial sequence-specific architectural DNA binding proteins that stiffen or kink looped DNA, impacting gene expression in opposite ways.

Realistic yields for small grain forages in Iowa will provide data to make economic decisions on spring forage crops. Both yield and nutrient levels will help producers determine if this double-cropping option is feasible to implement, and if it can supply adequate protein levels in cattle diets. Data from the plots will be shared through eastern Iowa grazing and cover crop programs and field days.

A winter annual/summer annual forage system can be used to break up the traditional corn/soybean rotation and produce 6-7 tons of forage feed on a dry matter basis. Because these are all grass forages, they tend to respond positively to additional nitrogen fertilizer with increased dry matter yields, crude protein and energy levels.

Purpose Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. Methods From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. Results The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. Conclusion Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

Background Whether egg consumption is associated with the risk of type 2 diabetes (T2D) remains unsettled. Objectives We evaluated the association between egg consumption and T2D risk in 3 large US prospective cohorts, and performed a systematic review and meta-analysis of prospective cohort studies. Methods We followed 82,750 women from the Nurses' Health Study (NHS; 1980-2012), 89,636 women from the NHS II (1991-2017), and 41,412 men from the Health Professionals Follow-up Study (HPFS; 1986-2016) who were free of T2D, cardiovascular disease, and cancer at baseline. Egg consumption was assessed every 2-4 y using a validated FFQ. We used Cox proportional hazard models to estimate HRs and 95% CIs. Results During a total of 5,529,959 person-years of follow-up, we documented 20,514 incident cases of T2D in the NHS, NHS II, and HPFS. In the pooled multivariable model adjusted for updated BMI, lifestyle, and dietary confounders, a 1-egg/d increase was associated with a 14% (95% CI: 7%, 20%) higher T2D risk. In random-effects meta-analysis of 16 prospective cohort studies (589,559 participants; 41,248 incident T2D cases), for each 1 egg/d, the pooled RR of T2D was 1.07 (95% CI: 0.99, 1.15; I2 = 69.8%). There were, however, significant differences by geographic region (P for interaction = 0.01). Each 1 egg/d was associated with higher T2D risk among US studies (RR: 1.18; 95% CI: 1.10, 1.27; I2 = 51.3%), but not among European (RR: 0.99; 95% CI: 0.85, 1.15; I2 = 73.5%) or Asian (RR: 0.82; 95% CI: 0.62, 1.09; I2 = 59.1%) studies. Conclusions Results from the updated meta-analysis show no overall association between moderate egg consumption and risk of T2D. Whether the heterogeneity of the associations among US, European, and Asian cohorts reflects differences in egg consumption habits warrants further investigation.This systematic review was registered at www.crd.york.ac.uk/prospero as CRD42019127860.

Intervertebral disc extrusion (IVDE) is the most common cause of spinal cord compression in dogs, whose prognosis is variable and depends on several factors, with deep pain perception (DPP) being the main parameter used. Investigations of new prognostic factors are studied to assist in the estimation of functional recovery. Thus, this study aimed to evaluate whether spinal hyperesthesia (SH) at the compression site can be used as a prognostic factor for the functional recovery of dogs with acute IVDE (Hansen type I), without DPP being subjected to thoracolumbar hemilaminectomy. Decompression surgery was performed on the same day or the day after admission. The duration of the loss of DPP until surgery performance ranged from 1 to 60 days, with a median of 4.5 days for the group of dogs with SH and 5.5 days for those without SH. Among the 68 dogs included in this retrospective study, 73.5% (50/68) showed SH, and 26.5% (18/68) were not identified. Recovery was satisfactory in 60% (30/50) of dogs with SH and in 27.7% (5/18) of dogs without SH, demonstrating that paraplegic dogs without DPP but with SH were 3.9 times more likely to recover when compared to dogs in the same condition, but with no SH. No studies have evaluated SH by palpation of the spine as a prognostic factor, which reinforces the relevance of the present study. The results of this study imply that SH in paraplegic dogs affected by thoracolumbar IVDE, without the presence of DPP, can be used as a possible prognostic indicator of functional recovery. RESUMO: A extrusão do disco intervertebral (EDIV) é a causa mais comum de lesão compressiva na medula espinhal de cães, cujo prognóstico é variável e depende de diversos fatores, sendo a percepção de dor profunda (PDP) o principal parâmetro utilizado. Pesquisas de novos fatores prognósticos são estudados com intuito de auxiliar na estimativa mais precisa de recuperação funcional. Com isso, o objetivo do estudo foi avaliar se a hiperestesia espinhal (HE) no local da compressão, pode ser utilizada como um fator prognóstico para recuperação funcional de cães com extrusão aguda do disco intervertebral (Hansen tipo I), sem a presença de PDP submetidos a hemilaminectomia toracolombar. A cirurgia descompressiva ocorreu no mesmo dia ou no dia seguinte ao atendimento. A duração da perda de dor profunda até a realização da cirurgia variou de 1 a 60 dias, com uma mediana de 4,5 dias para o grupo de cães com e 5,5 dias para aqueles sem hiperestesia espinhal. Dos 68 cães incluídos nesse estudo retrospectivo, 73,5% (50/68) apresentavam HE e, em 26,5% (18/68) a dor não foi identificada. A recuperação foi satisfatória nos cães com HE em 60% (30/50) e, sem HE, em 27,7% (5/18) dos casos, demonstrando que os cães paraplégicos sem PDP, mas com presença de hiperestesia espinhal tem 3,9 vezes mais chances de recuperação quando comparado com cães na mesma condição, mas sem HE. Não foram encontrados trabalhos que avaliaram a HE mediante a palpação da coluna vertebral como um fator prognóstico, o que reforça a relevância do presente estudo. Os resultados do presente trabalho sugerem que a HE em cães paraplégicos acometidos por EDIV toracolombar sem presença de PDP pode ser utilizada como um possível indicador prognóstico de recuperação funcional.

Cerebrospinal fluid (CSF) collection in dogs with brain neoplasms (BN) may be associated with complications owing to increased intracranial pressure caused by expansive lesions. Although this procedure has been performed in dogs with BN, no data regarding complications after CSF tap in these animals is available. Thus, this retrospective study aimed to identify the rate and types of complications observed after CSF taps in dogs with BN. Thirty dogs with BN were included in the study. In 83% (25/30) of the cases, clinical recovery after CSF tap was considered normal, and in 17% (5/30) the recovery was abnormal. The main clinical and neurological signs observed in dogs with abnormal clinical recovery were apnea (5/5), absence of pupillary photomotor reflex (3/5), coma (2/5), and stupor (1/5). In 40% (2/5) of the dogs, herniation of the cerebellum through the foramen magnum was observed on necropsy. In conclusion, the rate of complications after CSF taps was 17%, and was characterized by apnea, absent pupillary photomotor reflex, altered level of consciousness, and encephalic herniation.

Alterations in the

Atomic force microscopy (AFM) has been consistently supporting nanosciences and nanotechnologies for over 30 years and is used in many fields from condensed matter physics to biology. It enables the measurement of very weak forces at the nanoscale, thus elucidating the interactions at play in fundamental processes. Here, we leverage the combined benefits of micro/nanoelectromechanical systems and cavity optomechanics to fabricate a sensor for dynamic mode AFM at a frequency above 100 MHz. This frequency is two decades above the fastest commercial AFM probes, suggesting an opportunity for measuring forces at timescales unexplored thus far. The fabrication is achieved using very-large-scale integration technologies derived from photonic silicon circuits. The probe’s optomechanical ring cavity is coupled to a 1.55 μm laser light and features a 130 MHz mechanical resonance mode with a quality factor of 900 in air. A limit of detection in the displacement of 3 × 10−16 m/√Hz is obtained, enabling the detection of the Brownian motion of the probe and paving the way for force sensing experiments in the dynamic mode with a working vibration amplitude in the picometer range. When inserted in a custom AFM instrument embodiment, this optomechanical sensor demonstrates the capacity to perform force-distance measurements and to maintain a constant interaction strength between the tip and sample, an essential requirement for AFM applications. Experiments indeed show a stable closed-loop operation with a setpoint of 4 nN/nm for an unprecedented subpicometer vibration amplitude, where the tip–sample interaction is mediated by a stretched water meniscus.

Mitochondria are a dynamic eukaryotic innovation that play diverse roles in biology and disease. The mitochondrial genome is remarkably conserved in all vertebrates, encoding the same 37-gene set and overall genomic structure, ranging from 16,596 base pairs (bp) in the teleost zebrafish (Danio rerio) to 16,569 bp in humans. Mitochondrial disorders are amongst the most prevalent inherited diseases, affecting roughly 1 in every 5000 individuals. Currently, few effective treatments exist for those with mitochondrial ailments, representing a major unmet patient need. Mitochondrial dysfunction is also a common component of a wide variety of other human illnesses, ranging from neurodegenerative disorders such as Huntington’s disease and Parkinson’s disease to autoimmune illnesses such as multiple sclerosis and rheumatoid arthritis. The electron transport chain (ETC) component of mitochondria is critical for mitochondrial biology and defects can lead to many mitochondrial disease symptoms. Here, we present a publicly available collection of genetic mutants created in highly conserved, nuclear-encoded mitochondrial genes in Danio rerio. The zebrafish system represents a potentially powerful new opportunity for the study of mitochondrial biology and disease due to the large number of orthologous genes shared with humans and the many advanced features of this model system, from genetics to imaging. This collection includes 15 mutant lines in 13 different genes created through locus-specific gene editing to induce frameshift or splice acceptor mutations, leading to predicted protein truncation during translation. Additionally, included are 11 lines created by the random insertion of the gene-breaking transposon (GBT) protein trap cassette. All these targeted mutant alleles truncate conserved domains of genes critical to the proper function of the ETC or genes that have been implicated in human mitochondrial disease. This collection is designed to accelerate the use of zebrafish to study many different aspects of mitochondrial function to widen our understanding of their role in biology and human disease.

Measuring the roll angle of single-track vehicles has always been a challenging task; however, accurate and reliable measurements of this magnitude are paramount for controlling the stabili...

Gestational trophoblastic disease (GTD) is a heterogeneous group of lesions arising from placental tissue. Epithelioid trophoblastic tumor (ETT), derived from chorionic-type trophoblast, is the rarest form of GTD with only approximately 130 cases described in the literature. Due to its morphologic mimicry of epithelioid smooth muscle tumors and carcinoma, ETT can be misdiagnosed. To date, molecular characterization of ETTs is lacking. Furthermore, ETT is difficult to treat when disease spreads beyond the uterus. Here using RNA-Seq analysis in a cohort of ETTs and other gestational trophoblastic lesions we describe the discovery of LPCAT1-TERT fusion transcripts that occur in ETTs and coincide with underlying genomic deletions. Through cell-growth assays we demonstrate that LPCAT1-TERT fusion proteins can positively modulate cell proliferation and therefore may represent future treatment targets. Furthermore, we demonstrate that TERT upregulation appears to be a characteristic of ETTs, even in the absence of LPCAT1-TERT fusions, and that it appears linked to copy number gains of chromosome 5. No evidence of TERT upregulation was identified in other trophoblastic lesions tested, including placental site trophoblastic tumors and placental site nodules, which are thought to be the benign chorionic-type trophoblast counterpart to ETT. These findings indicate that LPCAT1-TERT fusions and copy-number driven TERT activation may represent novel markers for ETT, with the potential to improve the diagnosis, treatment, and outcome for women with this rare form of GTD.

Background GNB1 encodes a subunit of a heterotrimeric G‐protein complex that transduces intracellular signaling cascades. Disruptions to the gene have previously been shown to be embryonic lethal in knockout mice and to cause complex neurodevelopmental disorders in humans. To date, the majority of variants associated with disease in humans have been missense variants in exons 5‐7. Methods Genetic sequencing was performed on two patients presenting with complex neurological phenotypes including intellectual disability, hypotonia, and in one patient seizures. Reported variants were assessed using RNA sequencing and functional BRET/BiFC assays. Results A splice variant reported in patient 1 was confirmed to cause usage of a cryptic splice site leading to a truncated protein product. Patient 2 was reported to have a truncating variant. BRET and BiFC assays of both patient variants confirmed both were deficient in inducing GPCR‐induced G protein activation due to lack of dimer formation with the Gγ subunit. Conclusion Here, we report two patients with functionally confirmed loss of function variants in GNB1 and neurodevelopmental phenotypes including intellectual disability, hypotonia, and seizures in one patient. These results suggest haploinsufficiency of GNB1 is a mechanism for neurodevelopmental disorders in humans., Missense variants in GNB1 are associated with a complex neurodevelopmental disorder. Here we present two additional patients with overlapping phenotypes including developmental delay, hypotonia, intellectual disability, and seizures in one patient. Both patients have presumed loss‐of‐function variants which we have shown functionally to cause loss of protein function, thus adding evidence that haploinsufficiency is a disease mechanism associated with GNB1.

Gene regulation by control of transcription initiation is a fundamental property of living cells. Much of our understanding of gene repression originated from studies of the E. coli lac operon switch, where DNA looping plays an essential role. To validate and generalize principles from lac for practical applications, we previously described artificial DNA looping driven by designed Transcription Activator-Like Effector Dimer (TALED) proteins. Because TALE monomers bind the idealized symmetrical lac operator sequence in two orientations, our prior studies detected repression due to multiple DNA loops. We now quantitatively characterize gene repression in living E. coli by a collection of individual TALED loops with systematic loop length variation. Fitting of a thermodynamic model allows unequivocal demonstration of looping and comparison of the engineered TALED repression system with the natural lac repressor system.Statement of SignificanceWe are designing and testing in living bacteria artificial DNA looping proteins engineered based on principles learned from studies of the E. coli lac repressor. The engineered proteins are based on artificial dimers of Transcription Activator-Like Effector (TALE) proteins that have programmable DNA binding specificities. The current work is the first to create unique DNA repression loops using this approach. Systematic study of repression as a function of loop size, with data fitting to a thermodynamic model, now allows this system to be compared in detail with lac repressor loops, and relevant biophysical parameters to be estimated. This approach has implications for the artificial regulation of gene expression.

A review of the current use of multibody dynamics methods in the analysis of the dynamics of vehicles is given. Railway vehicle dynamics as well as road vehicle dynamics are considered, where for the latter the dynamics of cars and trucks and the dynamics of single-track vehicles, in particular motorcycles and bicycles, are reviewed. Commonalities and differences are shown, and open questions and challenges are given as directions for further research in this field.

This paper is part of the Proceedings of the 2019 Bicycle and Motorcycle Dynamics Conference: A Symposium on the Dynamics and Control of Single Track Vehicles held in Padova, Italy September 9th through 11th in the year 2019.Artifact ID: 7

Alterations in the TAOK1 gene have recently emerged as the cause of developmental delay with or without intellectual impairment or behavioral abnormalities (MIM #619575). The thirty-two cases currently described in the literature have predominantly de novo alterations in TAOK1 and a wide spectrum of neurodevelopmental abnormalities. Here, we report four patients with novel pathogenic TAOK1 variants identified by research genome sequencing, clinical exome sequencing, and international matchmaking. The overlapping clinical features of our patients are consistent with the emerging core phenotype of TAOK1-associated syndrome: facial dysmorphism, feeding difficulties, global developmental delay, joint laxity, and hypotonia. However, behavioral abnormalities and gastrointestinal issues are more common in our cohort than previously reported. Two patients have de novo TAOK1 variants (one missense, one splice site) consistent with most known alterations in this gene. However, we also report the first sibling pair who both inherited a TAOK1 frameshift variant from a mildly affected mother. Our findings suggest that incomplete penetrance and variable expressivity are relatively common in TAOK1-associated syndrome, which holds important implications for clinical genetic testing.

The quantification of mechanical power can provide valuable insight into athlete performance because it is the mechanical principle of the rate at which the athlete does work or transfers energy to complete a movement task. Estimates of power are usually limited by the capabilities of measurement systems, resulting in the use of simplified power models. This review provides a systematic overview of the studies on mechanical power in sports, discussing the application and estimation of mechanical power, the consequences of simplifications, and the terminology. The mechanical power balance consists of five parts, where joint power is equal to the sum of kinetic power, gravitational power, environmental power, and frictional power. Structuring literature based on these power components shows that simplifications in models are done on four levels, single vs multibody models, instantaneous power (IN) versus change in energy (EN), the dimensions of a model (1D, 2D, 3D), and neglecting parts of the mechanical power balance. Quantifying the consequences of simplification of power models has only been done for running, and shows differences ranging from 10% up to 250% compared to joint power models. Furthermore, inconsistency and imprecision were found in the determination of joint power, resulting from inverse dynamics methods, incorporation of translational joint powers, partitioning in negative and positive work, and power flow between segments. Most inconsistency in terminology was found in the definition and application of 'external' and 'internal' work and power. Sport research would benefit from structuring the research on mechanical power in sports and quantifying the result of simplifications in mechanical power estimations.

Hypersensitivity reactions (HSRs) to chemotherapy is an ongoing issue in cancer treatments. Strategies to induce tolerance and maximize chemotherapy efficacy include desensitization protocols. The precise impact of these protocols, however, in the long-term treatments remains unclear. We aim to compare overall survival (OS) in hypersensitive patients treated with carboplatin desensitization to patients without hypersensitivity reactions. We also sought to identify new risk factors for HSRs and reconfirm that the DNA repair enzyme, germline BRCA1/2 (gBRCA1/2), is a risk factor for hypersensitivity. Retrospective study in patients with ovarian cancer tested for gBRCA1/2 mutations who received more than six infusions of carboplatin from August 2005 to November 2016. Two-sided Fisher exact, Student’s t test and Gehan–Breslow–Wilcoxon test were used for statistical analysis. Univariate and multivariate analyses were completed to identify independent predictors of survival. Statistical significance was set with a two-sided p value of 0.05. Ninety-one patients with gBRCA1/2 testing met inclusion. Forty patients (44%) were gBRCA1/2-deficient and 51 (56%) were gBRCA1/2-proficient. Patients with gBRCA1/2 deficiencies had a higher likelihood of developing carboplatin hypersensitivity, HR 6.433 (95% CI: 1.868–22.149). None of the patients with carboplatin hypersensitivity were given PARP inhibitors prior to the development of HSRs. The patients with recurrent advanced stage (III–IV) ovarian cancer had a higher likelihood of developing carboplatin hypersensitivity, HR 4.783 (1.008–22.689). Moreover, we found that hypersensitive patients who underwent carboplatin desensitization had a 48-month longer OS than patients without hypersensitivity to carboplatin not undergoing carboplatin desensitization (p = 0.0094). A subgroup analysis indicated that gBRCA1/2-proficient hypersensitive patients undergoing carboplatin desensitization had a 43-month longer OS than gBRCA1/2-proficient patients without HSRs (p = 0.034). We confirmed that gBRCA1/2 deficiency and advanced stage are independent risk factors for development of carboplatin hypersensitivity in ovarian cancer patients. Our study also shows improved OS in hypersensitive patients receiving CD compared to non-hypersensitive patients, independent of gBRCA1/2.

Genetic switches must alternate between states whose probabilities are dependent on regulatory signals. Classical examples of transcriptional control in bacteria depend on repressive DNA loops anchored by proteins whose structures are sensitive to small molecule inducers or co-repressors. We are interested in exploiting these natural principles to engineer artificial switches for transcriptional control of bacterial genes. Here, we implement designed homodimeric DNA looping proteins (‘Transcription Activator-Like Effector Dimers’; TALEDs) for this purpose in living bacteria. Using well-studied FKBP dimerization domains, we build switches that mimic regulatory characteristics of classical Escherichia coli lactose, galactose and tryptophan operon promoters, including induction or co-repression by small molecules. Engineered DNA looping using TALEDs is thus a new approach to tuning gene expression in bacteria. Similar principles may also be applicable for gene control in eukaryotes.