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Fibrocystic changes are commonly seen in clinically symptomatic patients and during imaging workup of screening-detected findings. The term "fibrocystic changes" encompasses a broad spectrum of specific benign pathologic entities. Recognition of classically benign findings of fibrocystic changes, including cysts and layering calcifications, can prevent unnecessary follow-ups and biopsies. Imaging findings such as solid masses, nonlayering calcifications, and architectural distortion may require core needle biopsy for diagnosis. In these cases, understanding the varied appearances of fibrocystic change aids determination of radiologic-pathologic concordance. Management of fibrocystic change is typically conservative., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Porcine epidemic diarrhea virus (PEDV) causes a highly contagious enteric disease with major economic losses to swine production worldwide. Due to the immaturity of the neonatal piglet immune system and given the high virulence of PEDV, improving passive lactogenic immunity is the best approach to protect suckling piglets against the lethal infection. We tested whether oral vitamin A (VA) supplementation and PEDV exposure of gestating and lactating VA-deficient (VAD) sows would enhance their primary immune responses and boost passive lactogenic protection against the PEDV challenge of their piglets. We demonstrated that PEDV inoculation of pregnant VAD sows in the third trimester provided higher levels of lactogenic protection of piglets as demonstrated by >87% survival rates of their litters compared with <10% in mock litters and that VA supplementation to VAD sows further improved the piglets' survival rates to >98%. We observed significantly elevated PEDV IgA and IgG antibody (Ab) titers and Ab-secreting cells (ASCs) in VA-sufficient (VAS)+PEDV and VAD+VA+PEDV sows, with the latter maintaining higher Ab titers in blood prior to parturition and in blood and milk throughout lactation. The litters of VAD+VA+PEDV sows also had the highest serum PEDV-neutralizing Ab titers at piglet post-challenge days (PCD) 0 and 7, coinciding with higher PEDV IgA ASCs and Ab titers in the blood and milk of their sows, suggesting an immunomodulatory role of VA in sows. Thus, sows that delivered sufficient lactogenic immunity to their piglets provided the highest passive protection against the PEDV challenge. Maternal immunization during pregnancy (± VA) and VA sufficiency enhanced the sow primary immune responses, expression of gut-mammary gland trafficking molecules, and passive protection of their offspring. Our findings are relevant to understanding the role of VA in the Ab responses to oral attenuated vaccines that are critical for successful maternal vaccination programs against enteric infections in infants and young animals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Amimo, Michael, Chepngeno, Jung, Raev, Paim, Lee, Damtie, Vlasova and Saif.)

Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial., (© 2024. The Author(s).)

Major histocompatibility complex (MHC)-Associated Peptide Proteomics (MAPPs) is an ex vivo method used to assess the immunogenicity risk of biotherapeutics. MAPPs can identify potential T-cell epitopes within the biotherapeutic molecule. Using adalimumab treated human monocyte derived dendritic cells (DCs) and a pan anti-HLA-DR antibody (Ab), we systematically automated and optimized biotin/streptavidin (SA)-capture antibody coupling, lysate incubation with capture antibody, as well as the washing and elution steps of a MAPPs method using functionalized magnetic beads and a KingFisher Magnetic Particle processor. Automation of these steps, combined with capturing using biotinylated-Ab/SA magnetic beads rather than covalently bound antibody, improved reproducibility as measured by minimal inter-and intra-day variability, as well as minimal analyst-to-analyst variability. The semi-automated MAPPs workflow improved sensitivity, allowing for a lower number of cells per analysis. The method was assessed using five different biotherapeutics with varying immunogenicity rates ranging from 0.1 to 48% ADA incidence in the clinic. Biotherapeutics with ≥10%immunogenicity incidence consistently presented more peptides (1.8-28 fold) and clusters (10-21 fold) compared to those with <10% immunogenicity incidence. Our semi-automated MAPPs method provided two main advantages over a manual workflow- the robustness and reproducibility affords confidence in the epitopes identified from as few as 5 to 10 donors and the method workflow can be readily adapted to incorporate different capture Abs in addition to anti-HLA-DR. The incorporation of semi-automated MAPPs with biotinylated-Ab/SA bead-based capture in immunogenicity screening strategies allows the generation of more consistent and reliable data, helping to improve immunogenicity prediction capabilities in drug development. MHC associated peptide proteomics (MAPPs), Immunogenicity risk assessment, in vitro /ex vivo, biotherapeutics, Major Histocompatibility Complex Class II (MHC II), LC-MS, Immunoaffinity Capture, streptavidin magnetic beads., Competing Interests: All authors are or were employed by Genentech, a member of the Roche Group when this work was executed., (Copyright © 2023 Lee, Saad, Wong, LaMar, Kamen, Ordonia, Melendez, Hassanzadeh, Chung and Kaur.)

Background: To promote the rational use of cardiovascular imaging in patients with congenital heart disease, the American College of Cardiology developed Appropriate Use Criteria (AUC), but its clinical application and pre-release benchmarks have not been evaluated. We aimed to evaluate the appropriateness of indications for cardiovascular magnetic resonance (CMR) and cardiovascular computed tomography (CCT) in patients with conotruncal defects and to identify factors associated with maybe or rarely appropriate (M/R) indications., Methods: Twelve centers each contributed a median of 147 studies performed prior to AUC publication (01/2020) on patients with conotruncal defects. To incorporate patient characteristics and center-level effects, a hierarchical generalized linear mixed model was used., Results: Of the 1753 studies (80% CMR, and 20% CCT), 16% were rated M/R. Center M/R ranged from 4 to 39%. Infants accounted for 8.4% of studies. In multivariable analyses, patient- and study-level factors associated with M/R rating included: age <1 year (OR 1.90 [1.15-3.13]), truncus arteriosus (vs. tetralogy of Fallot, OR 2.55 [1.5-4.35]), and CCT (vs. CMR, OR 2.67 [1.87-3.83]). None of the provider- or center-level factors reached statistical significance in the multivariable model., Conclusions: Most CMRs and CCTs ordered for the follow-up care of patients with conotruncal defects were rated appropriate. However, there was significant center-level variation in appropriateness ratings. Younger age, CCT, and truncus arteriosus were independently associated with higher odds of M/R rating. These findings could inform future quality improvement initiatives and further exploration of factors resulting in center-level variation., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

Rotavirus A (RVA) causes ~200,000 diarrheal deaths annually in children <5yrs, mostly in low- and middle-income countries. Risk factors include nutritional status, social factors, breastfeeding status, and immunodeficiency. We evaluated the effects of vitamin A (VA) deficiency/VA supplementation and RVA exposure (anamnestic) on innate and T cell immune responses in RVA seropositive pregnant and lactating sows and passive protection of their piglets post-RVA challenge. Sows were fed VA deficient (VAD) or sufficient (VAS) diets starting at gestation day (GD)30. A subset of VAD sows received VA supplementation from GD|76 (30,000IU/day, VAD+VA). Sows (6 groups) were inoculated with porcine RVA G5P[7] (OSU strain) or Minimal Essential Medium (mock) at GD~90: VAD+RVA; VAS+RVA; VAD+VA+RVA; VAD-mock; VAS-mock; and VAD+VA-mock. Blood, milk, and gut-associated tissues were collected from sows at several time points to examine innate [natural killer (NK), dendritic (DC) cells], T cell responses and changes in genes involved in the gut-mammary gland (MG)-immunological axis trafficking. Clinical signs of RVA were evaluated post inoculation of sows and post-challenge of piglets. We observed decreased frequencies of NK cells, total and MHCII + plasmacytoid DCs, conventional DCs, CD103 + DCs and CD4 + /CD8 + and T regulatory cells (Tregs) and NK cell activity in VAD+RVA sows. Polymeric Ig receptor and retinoic acid receptor alpha (RARα) genes were downregulated in mesenteric lymph nodes and ileum of VAD+RVA sows. Interestingly, RVA-specific IFN-γ producing CD4 + /CD8 + T cells were increased in VAD-Mock sows, coinciding with increased IL-22 suggesting inflammation in these sows. VA supplementation to VAD+RVA sows restored frequencies of NK cells and pDCs, and NK activity, but not tissue cDCs and blood Tregs. In conclusion, similar to our recent observations of decreased B cell responses in VAD sows that led to decreased passive immune protection of their piglets, VAD impaired innate and T cell responses in sows, while VA supplementation to VAD sows restored some, but not all responses. Our data reiterate the importance of maintaining adequate VA levels and RVA immunization in pregnant and lactating mothers to achieve optimal immune responses, efficient function of the gut-MG-immune cell-axis and to improve passive protection of their piglets., Competing Interests: Author DD was employed by The Ohio State University Global One Health LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chepngeno, Amimo, Michael, Raev, Jung, Lee, Damtie, Omwando, Vlasova and Saif.)

The aim of this study was to determine the impact of vitamin A deficiency (VAD)/supplementation (±VA) and group A RV (RVA) maternal immunization of RVA seropositive multiparous pregnant sows, on their immune responses (anamnestic response) and on passive protection of their piglets against RVA challenge. Our results showed that VAD- mock sows had increased RVA RNA shedding at 1-5 days post piglet RVA challenge, and their litters had increased RVA shedding and diarrhea frequency throughout the experiment. VAD decreased memory B cell frequencies while VA supplementation increased RVA specific IgA/IgG antibody (Ab) secreting cell (ASC) numbers in blood, milk, and tissues of RVA inoculated VAD sows. The increased numbers of RVA specific IgA/IgG ASCs in blood, milk/colostrum, intestinal contents, and tissues in VA supplemented VAD sows, suggest a role of VA in B cell immunity and trafficking to tissues. We also observed that RVA inoculated sows had the highest viral neutralizing Ab titers in serum and milk while VA supplementation of VAD sows and RVA inoculation increased IgA + B cell frequencies in sow colostrum. In summary, we demonstrated that daily oral VA-supplementation (2nd trimester-throughout lactation) to RVA inoculated VAD sows improved the function of their gut-mammary-IgA immunological axis, reducing viral RNA shedding, diarrhea, and increasing weight gain in suckling piglets.

Objective: The objective of this study was to assess trends in screening breast MRI utilization among privately insured women in the U.S. from 2007 to 2017., Methods: The utilization of screening breast MRI among women aged 25-64 years from January 1, 2007, to December 31, 2017, was obtained using the MarketScan Commercial Database. We used Current Procedural Terminology codes to exclude breast MRI exams performed in women with a new breast cancer diagnosis and in women imaged to assess response to neoadjuvant therapy in the preceding 90 days. During the 11-year study, 351 763 study-eligible women underwent 488 852 MRI scans., Results: An overall 55.0% increase in screening breast MRI utilization was observed over the study period, with a steadily increasing trend. The greatest annual increase in percent utilization was from 2007 to 2008 at 16.6%. The highest utilization rate was in 2017, in which 0.4% of women aged 25-64 years underwent screening breast MRI. Of the women who underwent screening MRI with sufficient follow-up, 76.5% underwent only one examination during the study period., Conclusion: Utilization of screening breast MRI has increased steadily in the past decade to a peak of 0.4% of adult women. However, an estimated 9% of U.S. women are eligible for high-risk breast MRI screening; thus, utilization falls short of optimal compliance. Further studies to evaluate the barriers to screening compliance may help optimize utilization., (© Society of Breast Imaging 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Polatuzumab vedotin (or POLIVY ® ), an antibody-drug conjugate (ADC) composed of a polatuzumab monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker, has been approved by the United States Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma (DLBCL). To support the clinical development of polatuzumab vedotin, we characterized the distribution, catabolism/metabolism, and elimination properties of polatuzumab vedotin and its unconjugated MMAE payload in Sprague Dawley rats. Several radiolabeled probes were developed to track the fate of different components of the ADC, with 125 I and 111 In used to label the antibody component and 3 H to label the MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes into normal or bile-duct cannulated rats, blood, various tissues, and excreta samples were collected over 7-14 days post-dose and analyzed for radioactivity and to characterize the metabolites/catabolites. The plasma radioactivity of polatuzumab vedotin showed a biphasic elimination profile similar to that of unconjugated polatuzumab but different from unconjugated radiolabeled MMAE, which had a fast clearance. The vast majority of the radiolabeled MMAE in plasma remained associated with antibodies, with a minor fraction as free MMAE and MMAE-containing catabolites. Similar to unconjugated mAb, polatuzumab vedotin showed a nonspecific distribution to multiple highly perfused organs, including the lungs, heart, liver, spleen, and kidneys, where the ADC underwent catabolism to release MMAE and other MMAE-containing catabolites. Both polatuzumab vedotin and unconjugated MMAE were mainly eliminated through the biliary fecal route (>90%) and a small fraction (<10%) was eliminated through renal excretion in the form of catabolites/metabolites, among which, MMAE was identified as the major species, along with several other minor species. These studies provided significant insight into ADC's absorption, distribution, metabolism, and elimination (ADME) properties, which supports the clinical development of POLIVY.

Invasive Staphylococcus aureus infection is a leading cause of infectious disease-related deaths because S. aureus survives within host phagocytic cells, from which the bacteria are not adequately eliminated using current antibiotic treatments. Anti- S. aureus THIOMAB antibody-antibiotic conjugate (TAC), an anti- S. aureus antibody conjugated with antibiotic payload dmDNA31, was designed to deliver antibiotics into phagocytes, thereby killing intracellular S. aureus Herein, we present the distribution, metabolism/catabolism, and elimination properties for this modality. The tissue distribution of TAC and the release and elimination of its payload dmDNA31 were characterized in rats using multiple approaches. Intravenous injection of unconjugated [ 14 C]dmDNA31 to rats resulted in a rapid clearance in both systemic circulation and tissues, with biliary secretion as the major route of elimination. Six major metabolites were identified. When [ 14 C]dmDNA31 was conjugated to an antibody as TAC and administered to rat intravenously, a sustained exposure was observed in both systemic circulation and tissues. The dmDNA31 in blood and tissues mainly remained in conjugated form after administering TAC, although minimal deconjugation of dmDNA31 from TAC was also observed. Several TAC catabolites were identified, which were mainly eliminated through the biliary-fecal route, with dmDNA31 and deacetylated dmDNA31 as the most abundant catabolites. In summary, these studies provide a comprehensive characterization of the distribution, metabolism/catabolism, and elimination properties of TAC. These data fully support further clinical development of TAC for the invasive and difficult-to-treat S. aureus infection. SIGNIFICANCE STATEMENT: The present studies provide a comprehensive investigation of the absorption, distribution, metabolism/catabolism, and elimination of the first antibody-antibiotic conjugate developed for the treatment of an infectious disease. Although many antibody-drug conjugates are in development for various disease indications, only a limited amount of absorption, distribution, metabolism/catabolism, and elimination information is available in the literature. This study demonstrates the use of radiolabeling technology to delineate the absorption, distribution, metabolism/catabolism, and elimination properties of a complex modality and help address the key questions related to clinical pharmacological studies., Competing Interests: All the authors are current employees of Genentech Inc., (Copyright © 2020 by The Author(s).)

Objective: The purpose of this study is to summarize the results of a survey distributed by the Society of Breast Imaging (SBI) to assess applicants' experience with the 2018 and 2019 Breast Imaging Fellowship Match process., Methods: In this institutional review board-exempt study, the SBI issued an anonymous survey to all matched applicants in an attempt to gauge their experience with the 2018 and 2019 Match process., Results: The survey was sent to all 2018 and 2019 matched applicants and 105/236 (45%) responses were received. The majority (75%, 79/105) of respondents reported a positive experience with the Match, with at least a 4/5 rating, and only 3% (5/105) reported a rating below 3/5. There was some improvement in 2019, with 86% (24/28) of respondents reporting at least a 4/5 rating compared to 71% (55/77) in 2018. No respondent reported a score below a 3/5 rating in 2019. The most commonly cited issues with the Match were the timing of the Match process, the need for a universal application, and the burden of travel. Location and program reputation were the two most important factors contributing to the final rank order of programs., Conclusion: The great majority of applicants felt that the Match created a positive experience. Planned areas of improvement include the implementation of a universal application, the transition to virtual interviews, and a condensed timeline. These measures are likely to increase applicant satisfaction and provide a fair and efficient experience for future breast radiologists., (© Society of Breast Imaging 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immunoaffinity (IA) LC-MS/MS pharmacokinetic (PK) assays are widely used in the field for antibody drug conjugates (ADCs) containing peptide linkers that are enzymatically cleavable, such as MC-ValCit-PAB. Conjugate PK assay strategies for these ADCs involve cleavage with cathepsin B or papain to release and measure the antibody-conjugated drug (acDrug) concentration. However, robust acDrug PK methods for disulfide-linked self-immolating ADCs are lacking as they are a different conjugation modality. We developed acDrug PK assays for next-generation disulfide-linked ADCs involving immunoaffinity capture, chemical cleavage, and LC-MS/MS. Disulfide-linked ADCs captured from plasma were chemically reduced at basic pH to release the linker-drug, followed by self-immolation to liberate the active drug, and quantified by MRM LC-MS/MS. Herein, we detail the development and optimization of this chemical cleavage acDrug PK assay, resulting in robust accuracy and precision (±20%). The conjugation site of the linker-drug on the antibody was found to affect the kinetics of drug release. Multiple biophysical and chemical characteristics, such as tertiary structure, fractional solvent accessibility, p K a of the conjugation site, surrounding residue's pI, and electrostatic charge, may directly impact the drug release kinetics. Similar site-specific stability has been previously reported for ADCs in vivo. The assay development and qualification data for this original assay format are presented along with its application to multiple in vitro and in vivo studies across species.

Somatic motor neurons are selectively vulnerable in spinal muscular atrophy (SMA), which is caused by a deficiency of the ubiquitously expressed survival of motor neuron protein. However, some motor neuron groups, including oculomotor and trochlear (ocular), which innervate eye muscles, are for unknown reasons spared. To reveal mechanisms of vulnerability and resistance in SMA, we investigate the transcriptional dynamics in discrete neuronal populations using laser capture microdissection coupled with RNA sequencing (LCM-seq). Using gene correlation network analysis, we reveal a TRP53-mediated stress response that is intrinsic to all somatic motor neurons independent of their vulnerability, but absent in relatively resistant red nucleus and visceral motor neurons. However, the temporal and spatial expression analysis across neuron types shows that the majority of SMA-induced modulations are cell type-specific. Using Gene Ontology and protein network analyses, we show that ocular motor neurons present unique disease-adaptation mechanisms that could explain their resilience. Specifically, ocular motor neurons up-regulate (1) Syt1 , Syt5 , and Cplx2 , which modulate neurotransmitter release; (2) the neuronal survival factors Gdf15, Chl1 , and Lif ; (3) Aldh4, that protects cells from oxidative stress; and (4) the caspase inhibitor Pak4. Finally, we show that GDF15 can rescue vulnerable human spinal motor neurons from degeneration. This confirms that adaptation mechanisms identified in resilient neurons can be used to reduce susceptibility of vulnerable neurons. In conclusion, this in-depth longitudinal transcriptomics analysis in SMA reveals novel cell type-specific changes that, alone and combined, present compelling targets, including Gdf15 , for future gene therapy studies aimed toward preserving vulnerable motor neurons., (© 2020 Nichterwitz et al.; Published by Cold Spring Harbor Laboratory Press.)

Purpose: The purpose of this study is to evaluate factors contributing to medical malpractice claims relating to breast cancer and the field of breast imaging., Method and Materials: A retrospective analysis of jury verdict and settlement reports in US state and federal courts on the Westlaw legal database was performed. The database was searched for 'malpractice' and 'breast cancer' related terms from 2005 to 2015. 253 cases were evaluated for factors including case outcome, award amounts, type of physician defendants, plaintiff age, stage at diagnosis, length of delay in diagnosis, and symptomatology, among other factors. Data were summarized using descriptive statistics. Logistic regression was used to evaluate associations between factors and plaintiff award., Results: Median plaintiff age was 46 (IQR 39, 56). In cases that resulted in plaintiff payment, the award amount was $978,858 ± 2,308,598. Delay in diagnosis was cited as a reason for claimed negligence in 82% of cases. Mean length of delay was 17 ± 13 months. Named defendants were radiologists (43%), surgeons (27%), obstetrician/gynecologists (26%), and internal medicine/family practice (15%). Age, defendant type, and cancer stage were not significant predictors of case outcome. Failure to refer to a surgeon was twofold (OR [95% CI]: 2.44 [1.085, 5.489]) more likely to be resolved with payment compared to those cases without that factor. Cases with a delay in diagnosis of ≥12 months were twofold (OR [95% CI]: 2.129 [1.086, 4.175]) more likely to be resolved with payment compared to a delay <12 months. Patients who failed to follow up as recommended were twofold (OR [95% CI]: 2.31 [1.05, 5.10]) less likely to have their case be resolved with payment., Conclusion: Plaintiffs involved in breast cancer imaging related medical malpractice cases tend to be younger than the median age of diagnosis of breast cancer for US women (62 per NCI Surveillance, Epidemiology and End Results data). Breast cancer imaging suits involve physicians from multiple specialties, radiology being the most common. Delay in diagnosis ≥12 months, lack of surgeon referral, and lack of recommended follow up are related to plaintiff payments and may be areas of professional practice to target as radiology professionals., Clinical Relevance/application: Medical malpractice relating to breast cancer and breast imaging remains very prevalent and costly for all involved. Radiologists are being named in these lawsuits more frequently than in the past., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This work discloses the first examples of antibody-drug conjugates (ADCs) that are constructed from linker-drugs bearing dimeric seco-CBI payloads (duocarmycin analogs). Several homogeneous, CD22-targeting THIOMAB antibody-drug conjugates (TDCs) containing the dimeric seco-CBI entities are shown to be highly efficacious in the WSU-DLCL2 and BJAB mouse xenograft models. Surprisingly, the seco-CBI-containing conjugates are also observed to undergo significant biotransformation in vivo in mice, rats, and monkeys and thereby form 1:1 adducts with the Alpha-1-Microglobulin (A1M) plasma protein from these species. Variation of both the payload mAb attachment site and length of the linker-drug is shown to alter the rates of adduct formation. Subsequent experiments demonstrated that adduct formation attenuates the in vitro antiproliferation activity of the affected seco-CBI-dimer TDCs, but does not significantly impact the in vivo efficacy of the conjugates. In vitro assays employing phosphatase-treated whole blood suggest that A1M adduct formation is likely to occur if the seco-CBI-dimer TDCs are administered to humans. Importantly, protein adduct formation leads to the underestimation of total antibody (Tab) concentrations using an ELISA assay but does not affect Tab values determined via an orthogonal LC-MS/MS method. Several recommendations regarding bioanalysis of future in vivo studies involving related seco-CBI-containing ADCs are provided based on these collective findings.

Objectives: To determine the number and characteristics of cancers detected and the optimal imaging evaluation in women presenting with focal breast pain (FBP)., Materials and Methods: We performed a retrospective review of 4720 women who underwent imaging for FBP from 2001 to 2013. Women 18 and over with one or two foci of breast pain and no concurrent breast symptoms were included. 944 patients met criteria. We recorded the imaging work-up, presence and type of finding at the site of pain, BI-RADS® assessment, and pathological outcomes. Subsequent imaging and clinical follow up was recorded., Results: Imaging evaluation consisted of sonogram alone in 286 women, mammogram alone in 231 women, and both in 427 women. 113 women had an imaging finding at the site of pain; 103 were designated benign or probably benign. 12 biopsies of corresponding findings were performed: 9 benign, 1 invasive lobular carcinoma, 1 invasive ductal carcinoma, 1 ductal carcinoma in situ. All three malignancies were seen mammographically; 2 had an ultrasound correlate. At initial evaluation, 4 incidental breast cancers were diagnosed remote from the site of FBP. All were seen on mammogram and 2 of 4 had an ultrasound correlate. On follow up evaluation, 9 cancers were diagnosed at the site of pain and 13 incidental cancers were diagnosed., Conclusion: FBP is rarely associated with malignancy. Targeted ultrasound may be deferred in women 40 and older with FBP, no other clinical findings, and a negative mammogram., (Copyright © 2019. Published by Elsevier Inc.)

Few treatment options are available for acute myeloid leukemia (AML) patients. DCLL9718A is an antibody-drug conjugate that targets C-type lectin-like molecule-1 (CLL-1). This receptor is prevalent on monocytes, neutrophils, and AML blast cells, and unlike CD33, is not expressed on hematopoietic stem cells, thus providing possible hematopoietic recovery. DCLL9718A comprises an anti-CLL-1 IgG1 antibody (MCLL0517A) linked to a pyrrolobenzodiazepine (PBD) dimer payload, via a cleavable disulfide-labile linker. Here, we characterize the in vitro and in vivo stability, the pharmacokinetics (PK) and pharmacodynamics (PD) of DCLL9718A and MCLL0517A in rodents and cynomolgus monkeys. Three key PK analytes were measured in these studies: total antibody, antibody-conjugated PBD dimer and unconjugated PBD dimer. In vitro, DCLL9718A, was stable with most (> 80%) of the PBD dimer payload remaining conjugated to the antibody over 96 hours. This was recapitulated in vivo with antibody-conjugated PBD dimer clearance estimates similar to DCLL9718A total antibody clearance. Both DCLL9718A and MCLL0517A showed linear PK in the non-binding rodent species, and non-linear PK in cynomolgus monkeys, a binding species. The PK data indicated minimal impact of conjugation on the disposition of DCLL9718A total antibody. Finally, in cynomolgus monkey, MCLL0517A showed target engagement at all doses tested (0.5 and 20 mg/kg) as measured by receptor occupancy, and DCLL9718A (at doses of 0.05, 0.1 and 0.2 mg/kg) showed strong PD activity as evidenced by notable reduction in monocytes and neutrophils.

Although the prevalence of malignancy in average risk women under age 40 presenting with a palpable breast abnormality is low, the management of benign-appearing palpable abnormalities remains controversial. This study assesses the imaging evaluation, subsequent management, and outcomes of women under age 40 presenting with a palpable area of concern. This study also evaluates the costs, utility, and outcomes of BI-RADS 3 assessment in this patient population. A single institution retrospective case review from July 2010 through June 2013 identified women under age 40 presenting with a new palpable breast abnormality. Diagnostic imaging evaluation was performed. BI-RADS assessments and recommendations were recorded prospectively. Outcome was determined by tissue diagnosis, 2 years of surveillance, or search of the hospital tumor registry. Performance measures were calculated. Among 1440 cases, 1052 were initially assessed as BI-RADS 1 or 2 (73.1%), 184 as BI-RADS 3 (12.8%), 182 as BI-RADS 4 (12.6%), and 22 as BI-RADS 5 (1.5%). In all, 30 breast malignancies were diagnosed (cancer yield 2.1%). All 30 cancers were initially categorized as BI-RADS 4 or 5. No BI-RADS 1, 2, or 3 findings proved malignant. The imaging evaluation sensitivity was 100%, specificity was 87.7%, and accuracy was 87.9%. The negative predictive value was 100% and the positive predictive value was 14.7%. Average risk women under age 40 presenting with a palpable abnormality have a low prevalence of breast cancer. Imaging evaluation has a high sensitivity and negative predictive value, thereby allowing for confident characterization and appropriate management recommendations. For palpable solid masses with benign imaging features in women under age 40, short-term interval follow-up with subsequent periodic imaging or clinical examination for a total of 2 years is a cost-effective and safe alternative to biopsy., (© 2018 Wiley Periodicals, Inc.)

Hypoplastic left heart syndrome (HLHS) is the second most common congenital heart disease associated with congenital diaphragmatic hernia (CDH). The reported survival rate of neonates with CDH and HLHS is only 1%-5%. We review our experience with CDH and HLHS and compare our outcomes with published literature. Retrospective review of all neonates with CDH and HLHS at our institution over a 10-year period was performed. The morphology of cardiac and diaphragm defects, clinical course, treatment strategies, and outcomes were reviewed, and an algorithmic approach was proposed. Five patients with CDH and HLHS were treated between 2006 and 2016. All had mitral stenosis with aortic stenosis. Four patients had a left-sided Bochdalek diaphragmatic hernia and 1 patient had a large bilateral Morgagni hernia. Two (2/4) of the Bochdalek hernias were associated with significant pulmonary hypoplasia and required patch closure of the CDH; both were palliated with percutaneous ductal stents and both died. Three patients underwent primary Norwood operation followed by repair of less severe CDH defect. All 3 patients are currently well and have survived bidirectional Glenn anastomosis; one patient is well after Fontan operation. Successful palliation of neonates with HLHS and associated CDH is possible in the current era. Outcome is determined primarily by the severity of the CDH and the degree of associated pulmonary hypoplasia. An algorithmic team approach is helpful in management of this difficult group of patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor-positive (ER + ) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER + /HER2 - breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1-21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. Clin Cancer Res; 23(15); 4055-65. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Harmful mutations of the BRCA tumor suppressor genes result in a greater lifetime risk for malignancy-breast and ovarian cancers in particular. An increased risk for male breast, fallopian tube, primary peritoneal, pancreatic, prostate, and colon cancers also has been reported. The BRCA gene is inherited in an autosomal dominant pattern and tends to be highly penetrant; thus, there is an increased incidence of these cancers in affected families. Compared with sporadic tumors, BRCA-associated malignancies have unique manifestations, clinical features, and pathologic profiles. Manifestation at an early patient age, high-grade tumors, and an aggressive clinical course are common features of BRCA-associated malignancies. Understanding the behavior of these cancers aids in identification of affected individuals and families, who can then make informed decisions regarding their future health. Enhanced screening, prophylactic surgery, and chemoprevention are options for managing cancer risk factors in these individuals. Imaging has an important role in the screening, evaluation, staging, and follow-up of BRCA-associated malignancies. Supplemental screening of BRCA mutation carriers often begins at an early age and is critical for early and accurate cancer diagnoses. The authors review the etiopathogenesis and imaging features of BRCA-associated malignancies, the importance of a multidisciplinary approach to determining the diagnosis, and the treatment of patients who have these mutations to improve their outcomes. © RSNA, 2017.

Cancers of the female genital system, particularly endometrial and ovarian cancers, can be associated with hereditary cancer syndromes such as hereditary breast and ovarian cancer and Lynch syndrome. Cancers that are found in the setting of a hereditary cancer syndrome are often unique in presentation, clinical features, and pathologic profiles when compared with sporadic tumors. This article reviews the hereditary cancer syndromes associated with gynecological malignancies, as well as the imaging findings and staging system of endometrial and ovarian cancers. These associations are important for proper patient screening, diagnosis, and treatment.

Organic-inorganic perovskite is a promising class of materials for photovoltaic applications and light emitting diodes. However, so far commercialization is still impeded by several drawbacks. Atomic-scale effects have been suggested to be possible causes, but an unequivocal experimental view at the atomic level is missing. Here, we present a low-temperature scanning tunneling microscopy study of single crystal methylammonium lead bromide CH3NH3PbBr3. Topographic images of the in situ cleaved perovskite surface reveal the real-space atomic structure. Compared to the bulk we observe modified arrangements of atoms and molecules on the surface. With the support of density functional theory we explain these by surface reconstruction and a substantial interplay of the orientation of the polar organic cations (CH3NH3)(+) with the position of the hosting anions. This leads to structurally and electronically distinct domains with ferroelectric and antiferroelectric character. We further demonstrate local probing of defects, which may also impact device performance.

The molecular order of organic semiconductors at the gate dielectric is the most critical factor determining carrier mobility in thin film transistors since the conducting channel forms at the dielectric interface. Despite its fundamental importance, this semiconductor-insulator interface is not well understood, primarily because it is buried within the device. We fabricated dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DNTT) thin film transistors by thermal evaporation in vacuum onto substrates held at different temperatures and systematically correlated the extracted charge mobility to the crystal grain size and crystal orientation. As a result, we identify a molecular layer of flat-lying DNTT molecules at the semiconductor-insulator interface. It is likely that such a layer might form in other material systems as well, and could be one of the factors reducing charge transport. Controlling this interfacial flat-lying layer may raise the ultimate possible device performance for thin film devices.

Stressed cells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown 'hubs' of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts. We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology., (© 2014 The Authors. Published under the terms of the CC BY 4.0 license.)

Among gonococcal isolates examined at the Hawaii State Laboratory Division from 2003 to 2011, the prevalence of elevated cefixime minimum inhibitory concentrations (MICs; ≥0.064 μg/mL) and elevated cefpodoxime MICs (≥0.19 μg/mL) increased over time. In contrast, few isolates exhibited elevated ceftriaxone MICs (≥0.094 μg/mL), and the prevalence of elevated ceftriaxone MICs did not change.

In this article, we propose a novel methodology for the formation of monodisperse regularly sized disks of several nanometer thickness and with diameters of less than 100 nm using Langmuir monolayers as fabrication media. An amphiphilic triimide, tri-n-dodecylmellitic triimide (1), was spread as a monolayer at the air-water interface with a water-soluble macrocyclic oligoamine, 1,4,7,10-tetraazacyclododecane (cyclen), in the subphase. The imide moieties of 1 act as hydrogen bond acceptors and can interact weakly with the secondary amine moieties of cyclen as hydrogen bond donors. The monolayer behavior of 1 was investigated through π-A isotherm measurements and Brewster angle microscopy (BAM). The presence of cyclen in the subphase significantly shifted isotherms and induced the formation of starfish-like microstructures. Transferred monolayers on solid supports were analyzed by reflection absorption FT-IR (FT-IR-RAS) spectroscopy and atomic force microscopy (AFM). The Langmuir monolayer transferred onto freshly cleaved mica by a surface touching (i.e., Langmuir-Schaefer) method contained disk-shaped objects with a defined height of ca. 3 nm and tunable diameter in the tens of nanometers range. Several structural parameters such as the disk height, molecular aggregation numbers in disk units, and 2D disk density per unit surface area are further discussed on the basis of AFM observations together with aggregate structure estimation and thermodynamic calculations. It should be emphasized that these well-defined structures are produced through simple routine procedures such as solution spreading, mechanical compression, and touching a substrate at the surface. The controlled formation of defined nanostructures through easy macroscopic processes should lead to unique approaches for economical, energy-efficient nanofabrication.

Self-assembly of interfaces is of great interest in physical and chemical domains. One of the most challenging targets is to obtain an optimal interface structure showing good electronic properties by solution-processing. Interfaces of semiconductor/semiconductor, semiconductor/insulator and insulator/insulator have been successfully manipulated to obtain high-performance devices. In this review we discuss a special class of interface, semiconductor/insulator interface, formed by vertical phase separation during spin-coating and focus on the versatile applications in organic field-effect transistors (OFETs). The formation of such an interface can be finished within tens of seconds and its mechanism is related to the materials, surfaces and dynamics. Fascinatingly, such self-assembly could be used to simplify the fabrication procedure, improve film spreading, change interfacial properties, modify semiconductor morphology, and encapsulate thin films. These merits lead to OFETs with high performance and good reliability. Also, the method is very suitable for combining with other solution-processed techniques such as patterning and post-annealing, which leads to facile paper electronics, in situ purification and single crystal formation. Research on this topic not only provides an in-depth understanding of self-assembly in solution processing, but also opens new paths towards flexible organic electronics.

A method for substrate-mediated reverse gene transfection was developed using a silica film composed of an upright-sheet network. The silica film with a dense upright-sheet network shows approximately double higher transgene expression efficiency than that of solution-based transfection.

We modified a dual-cell linear ion trap mass spectrometer to perform infrared multiphoton dissociation (IRMPD) in the low-pressure trap of a dual-cell quadrupole linear ion trap (dual-cell QLT) and perform large-scale IRMPD analyses of complex peptide mixtures. Upon optimization of activation parameters (precursor q-value, irradiation time, and photon flux), IRMPD subtly, but significantly, outperforms resonant-excitation collisional-activated dissociation (CAD) for peptides identified at a 1% false-discovery rate (FDR) from a yeast tryptic digest (95% confidence, p = 0.019). We further demonstrate that IRMPD is compatible with the analysis of isobaric-tagged peptides. Using fixed QLT rf amplitude allows for the consistent retention of reporter ions, but necessitates the use of variable IRMPD irradiation times, dependent upon precursor mass to charge (m/z). We show that IRMPD activation parameters can be tuned to allow for effective peptide identification and quantitation simultaneously. We thus conclude that IRMPD performed in a dual-cell ion trap is an effective option for the large-scale analysis of both unmodified and isobaric-tagged peptides.

We report on the first Neisseria gonorrhoeae isolate in the United States identified with high-level resistance to azithromycin. This report discusses the epidemiologic case investigation, the molecular studies of resistance-associated mutations and N. gonorrhoeae multiantigen sequence typing, and challenges posed by emerging gonococcal antimicrobial resistance.

The US Centers for Disease Control and Prevention recently updated its recommendations for treating sexually transmitted diseases (STDs). In this review we highlight new treatment recommendations for mitigating the increasing prevalence of antibiotic-resistant Neisseria gonorrhoeae, the emergence of azithromycin-resistant Treponema pallidum, and treatment options for bacterial vaginosis and venereal warts. We also cover epidemiologic trends for common STDs in Hawai'i.

We describe a mass spectrometry method, QuantMode, which improves accuracy of isobaric tag-based quantification by alleviating the pervasive problem of precursor interference, simultaneous isolation and fragmentation of impurities, through gas-phase purification. QuantMode analysis of a yeast sample 'contaminated' with interfering human peptides showed substantially improved quantitative accuracy compared to a standard scan, with a small loss of spectral identifications. This technique enables large-scale, multiplexed quantitative proteomics using isobaric tagging.

The transcriptome and proteome change dynamically as cells respond to environmental stress; however, prior proteomic studies reported poor correlation between mRNA and protein, rendering their relationships unclear. To address this, we combined high mass accuracy mass spectrometry with isobaric tagging to quantify dynamic changes in ~2500 Saccharomyces cerevisiae proteins, in biological triplicate and with paired mRNA samples, as cells acclimated to high osmolarity. Surprisingly, while transcript induction correlated extremely well with protein increase, transcript reduction produced little to no change in the corresponding proteins. We constructed a mathematical model of dynamic protein changes and propose that the lack of protein reduction is explained by cell-division arrest, while transcript reduction supports redistribution of translational machinery. Furthermore, the transient 'burst' of mRNA induction after stress serves to accelerate change in the corresponding protein levels. We identified several classes of post-transcriptional regulation, but show that most of the variance in protein changes is explained by mRNA. Our results present a picture of the coordinated physiological responses at the levels of mRNA, protein, protein-synthetic capacity, and cellular growth.

Hawaii currently ranks first among states for chlamydia screening of young women based on recent Healthcare Effectiveness Data and Information Set (HEDIS) measures and has consistently ranked in the top ten states in the US for annual reported chlamydia rates since 2002. A statewide provider survey was conducted in October 2007 and March 2008 to assess chlamydia screening practices and beliefs and identify potential barriers to screening. The overall reported screening rate for 15-19 year old females was 66.9% with significant differences by practice specialty (obstetrician/gynecologists were more likely to screen than family practitioners or pediatricians) and practice setting (higher rates of screening in non-private practice settings). Providers who were unaware of health plan reimbursement for screening and those who targeted screening only for clients perceived to be at "high risk" were significantly less likely to routinely provide screening. The Hawaii State Department of Health is currently working in consort with health care providers and the state's dominant health insurance carriers to address these issues through targeted provider educational interventions.

Hydrosilylation provides a route to form substituted silanes in solution. A similar reaction has been observed in the formation of covalent organic monolayers on a hydrogen-terminated silicon surface and is called thermal hydrosilylation. In solution, the mechanism requires a catalyst to add the basal silicon and saturating hydrogen to the C=C double bond. On the silicon surface, however, the reaction proceeds efficiently at 200 °C, initiated by visible light, and more slowly at room temperature in the dark. Such low activation energy barriers for the reactions on a surface relative to that required for solution hydrosilylation are remarkable, and although many explanations have been suggested, controversy still exists. In this work using a constrained molecular dynamics approach within the density functional theory framework, we show that the free energy activation barrier for abstraction of a hydrogen from silicon by an alkene molecule can be overcome by visible light or thermal excitation. Furthermore, we show that by concerted transfer of a hydrogen from the α-carbon to the β-carbon, a 1-alkene can insert its α-carbon into a surface Si-H bond to accomplish hydrosilylation.

Here we present the Coon OMSSA Proteomic Analysis Software Suite (COMPASS): a free and open-source software pipeline for high-throughput analysis of proteomics data, designed around the Open Mass Spectrometry Search Algorithm. We detail a synergistic set of tools for protein database generation, spectral reduction, peptide false discovery rate analysis, peptide quantitation via isobaric labeling, protein parsimony and protein false discovery rate analysis, and protein quantitation. We strive for maximum ease of use, utilizing graphical user interfaces and working with data files in the original instrument vendor format. Results are stored in plain text comma-separated value files, which are easy to view and manipulate with a text editor or spreadsheet program. We illustrate the operation and efficacy of COMPASS through the use of two LC-MS/MS data sets. The first is a data set of a highly annotated mixture of standard proteins and manually validated contaminants that exhibits the identification workflow. The second is a data set of yeast peptides, labeled with isobaric stable isotope tags and mixed in known ratios, to demonstrate the quantitative workflow. For these two data sets, COMPASS performs equivalently or better than the current de facto standard, the Trans-Proteomic Pipeline., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Using a large set of high mass accuracy and resolution ETD tandem mass spectra, we characterized ETD-induced neutral losses. From these data we deduced the chemical formula for 20 of these losses. Many of them have been previously observed in electron-capture dissociation (ECD) spectra, such as losses of the side chains of arginine, aspartic acid, glutamic acid, glutamine, asparagine, leucine, histidine, and carbamidomethylated cysteine residues. With this information, we examined the diagnostic value of these amino acid-specific losses. Among 1285 peptide-spectrum matches, 92.5% have agreement between neutral loss-derived peptide amino acid composition and the peptide sequences. Moreover, we show that peptides can be uniquely identified by using only the accurate precursor mass and amino acid composition based on neutral losses; the median number of sequence candidates from an accurate mass query is reduced from 21 to 8 by adding side chain loss information. Besides increasing confidence in peptide identification, our findings suggest the potential use of these diagnostic losses in ETD spectra to improve false discovery rate estimation and to enhance the performance of scoring functions in database search algorithms., (© American Society for Mass Spectrometry, 2011)