bluuebunny/crossref_metadata_2025 huggingface dataset:
The path to personalized treatment in advanced and metastatic biliary tract cancers: a review of new targeted therapies and immunotherapy
Authors: Demols Anne , Bucalau Ana-Maria , Mans Laura
Published: July 2022

Purpose of review

To summarize targeted therapies and immunotherapy as treatment for advanced/metastatic biliary tract cancers and discuss ongoing clinical trials.

Recent findings

For the first time since gemcitabine–cisplatin was set as the standard of care in first-line advanced/metastatic biliary tract cancers in the ABC-02 trial, the combination of durvalumab and gemcitabine–cisplatin has demonstrated a statistically significant improvement of median overall survival in the TOPAZ-1 phase 3 trial. The ABC-06 trial showed a significant increase of median overall survival for FOLFOX and active symptom control compared with active symptom control alone in second-line regardless of molecular and genetic alterations. However, faced with a heterogeneous cancer, patient prognosis remains poor, leaving room for new, personalized, treatment options such as targeted therapies. Efficacy of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors has been demonstrated in different phase 2 trials for previously treated intrahepatic cholangiocarcinomas harboring FGFR2 fusions. Ivosidenib increases significantly median progression-free survival in previously treated cholangiocarcinomas with isocitrate dehydrogenase-1 (IDH-1) mutation. Other targeted therapies are tested for tumors with HER2 amplifications/mutations, BRAFV600E mutations or KRASG12C mutations.

In this review, we aim to follow the changes in the treatment of these tumors, moving from very few chemotherapy options to immunotherapy and targeted therapies in the context of molecular selection of biliary tract cancers subtypes.
Evolving nonvasodilator treatment options for pulmonary arterial hypertension
Authors: Medrek Sarah , Melendres-Groves Lana
Published: July 2022

Purpose of review

With the establishment of vasodilator therapy as a mainstay of treatment for pulmonary arterial hypertension (PAH), new therapeutic approaches are needed to prevent the development of the vasculopathy associated with this disease. Many studies are currently underway to investigate nonvasodilator treatment options.

Recent findings

Modulation of bone morphogenic protein receptor type 2 (BMPR2) signaling with sotatercept showed promising results in phase 2 studies. Rituximab, an anti-CD20 monoclonal antibody, showed some signal for beneficial effect in patients with scleroderma-associated PAH. Studies evaluating agents including tocilizumab, selonsertib, bardoxolone, 10-nitro-9(E)-enoic acid (CXA-10) and intravenous iron have not shown acceptable efficacy in treating PAH.

Pharmacologic approaches for the treatment of PAH include altering of transforming growth factor β/BMPR2 signaling, proliferation via growth factors, immune response, oxidative stress, estrogen signaling, metabolism, and neurohormonal modulation. Other treatment modalities including pulmonary artery nerve denervation, stem cell therapy, and inter-atrial shunt formation are also being explored.
Update in approaches to pulmonary hypertension because of left heart disease
Authors: Kennedy Jamie L.W. , Mihalek Andrew D.
Published: July 2022

Purpose of review

Left heart disease is the most common cause of pulmonary hypertension. This review summarizes the current care of patients with pulmonary hypertension caused by left heart disease (PH-LHD) and discusses recent and active clinical trials in this patient population.

Recent findings

The primary focus of interventions aimed at treating PH-LHD address the treatment of left heart disease. Significant advancements in the treatment of heart failure with preserved ejection fraction (HFpEF), a frequent cause of PH-LHD, are supported in the current literature. Patients with residual pulmonary hypertension despite optimal treatment of left heart disease have poor outcomes. Yet, interventions targeting the pulmonary vasculature in PH-LHD patients have not demonstrated significant benefits in studies to date. Current work focuses on differentiating isolated postcapillary pulmonary hypertension (IpcPH) from combined precapillary and postcapillary pulmonary hypertension (CpcPH) in a clinically consistent manner. It is hopeful that thorough phenotyping of PH-LHD patients will translate into effective treatment strategies addressing pulmonary vascular disease.

Referral to centers of excellence, considerations for enrollment in clinical trials, and evaluation for transplant is recommended for patients with residual pulmonary hypertension despite optimal treatment of left heart disease, particularly those with CpcPH.
Environmental and occupational exposures in interstitial lung disease
Authors: Lee Cathryn T. , Feary Johanna , Johannson Kerri A.
Published: July 2022

Purpose of review

We highlight recent advances in the understanding of how environmental and occupational exposures increase the risk of developing interstitial lung disease (ILD), and how to evaluate a patient for potential exposures.

Recent findings

A review of emerging literature suggests that environmental and occupational exposures can be directly causal, as in the case of the pneumoconioses and smoking-related ILDs, or one of many contributors to disease, as in the case of idiopathic pulmonary fibrosis (IPF). Regardless of the level of association, exposures are clearly prevalent across all ILD subtypes studied.

Inhalational exposures are increasingly recognized as an important component in the development of ILDs, and novel exposure-disease associations continue to be discovered. These exposures represent potential opportunities for further understanding the pathobiology of disease and for the prevention of these often progressive and debilitating disorders. Prospective, comprehensive data collection regarding occupational and environmental exposures are needed in ILD patients to fully elucidate specific antigens and their relationships to disease incidence and outcomes. Systematically collected exposure information will also inform potential interventions to remediate exposures and thus mitigate the course of frequently progressive and fatal diseases.
Sexual violence experiences among adolescent and young adult males: a review to empower healthcare providers
Authors: Blackburn Katelin , Grubb Laura K. , Vargas Gabriela
Published: July 2022

Purpose of review

Despite 3–17% of adolescent and young adult males (AYAMs) experiencing sexual violence, there is a paucity of information regarding their sexual violence experiences leaving them vulnerable to dangerous and detrimental sequelae.

Recent findings

There is underreporting and under-discussion of AYAMs’ experiences of sexual violence, with disclosure influenced by societal perceptions of male sexuality, shame, and fear of discrimination. AYAMs experience sexual violence from individuals known to them, with many experiencing physical violence, threats, coercion, and electronic harassment. Intersectionality, previous traumas, inappropriate childhood exposures to sexually explicit situations, select online media consumption, and adverse childhood experiences (ACEs) increase the risk of sexual violence. AYAMs who experience sexual violence are at increased risk of re-victimization, perpetrating sexual violence, experiencing bodily harm, contracting sexually transmitted infections (STIs), and experiencing internalizing and externalizing symptoms, which can lead to significant morbidity and mortality. Research on male-specific protective and resilience factors is scarce and represents an ongoing need.

After reviewing AYAMs’ experiences of sexual violence, including risk and protective factors, media influences, detrimental sequelae, and resilience factors, we provide a screening framework to empower the healthcare provider (HCP) to champion tailored prevention, screening, intervention, and advocacy efforts to support AYAMs.
Monitoring of paediatric type 1 diabetes
Authors: Marks Brynn E. , Wolfsdorf Joseph I.
Published: July 2022

Purpose of review

This article reviews recent developments in methods used to monitor paediatric type 1 diabetes (T1D), including an examination of the role of glycated haemoglobin (haemoglobin A1c) and its limitations for long-term assessment of glycaemia in individual patients, self-monitoring of blood glucose, continuous glucose monitoring (CGM) systems and ketone monitoring.

Recent findings

Monitoring of glycemia and ketones, when indicated, is a cornerstone of paediatric T1D management and is essential to optimize glycaemic control. Ongoing technological advancements have led to rapid changes and considerable improvement in the methods used to monitor glucose concentrations in people with T1D. As a result of recent innovations that have enhanced accuracy and usability, CGM is now considered the optimal method for monitoring glucose concentrations and should be introduced soon after diagnosis of T1D.

Patients/families and healthcare providers must receive comprehensive education and proper training in the use of CGM and interpretation of the vast amounts of data. Future challenges include ensuring equal access to and optimizing clinical use of CGM to further improve T1D care and outcomes.
Metabolic dysfunction-associated fatty liver disease in obese youth with insulin resistance and type 2 diabetes
Authors: Mastromauro Concetta , Polidori Nella , Giannini Cosimo
Published: July 2022

Purpose of review

The aim of this review is to present the new definition of the disease, defining the epidemiology, risk factors with a particular attention to the role of insulin resistance (IR) and to define the main treatments explored.

Recent findings

Nonalcoholic fatty liver disease (NAFLD) was previously considered a primary liver disease, but it would be more correct to consider it a component of the metabolic syndrome (MetS) in which IR might play a key role. Based on these findings, it has been recently proposed to modify the classic term of NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) that better reflects the pathophysiology of this complex disease.

Currently, no treatments approved in childhood are available, thus the only recommended approach is the prevention and correction of the known risk factors, and particularly of IR. However, further studies are needed to better clarify the pathogenetic mechanisms of NAFLD in order to establish more tailored therapies.
Advancements and future directions in the teamwork, targets, technology, and tight control—the 4T study: improving clinical outcomes in newly diagnosed pediatric type 1 diabetes
Authors: Zaharieva Dessi P. , Bishop Franziska K. , Maahs David M.
Published: July 2022

Purpose of review

The benefits of intensive diabetes management have been established by the Diabetes Control and Complications Trial. However, challenges with optimizing glycemic management in youth with type 1 diabetes (T1D) remain across pediatric clinics in the United States. This article will review our Teamwork, Targets, Technology, and Tight Control (4T) study that implements emerging diabetes technology into clinical practice with a team approach to sustain tight glycemic control from the onset of T1D and beyond to optimize clinical outcomes.

Recent findings

During the 4T Pilot study and study 1, our team-based approach to intensive target setting, education, and remote data review has led to significant improvements in hemoglobin A1c throughout the first year of T1D diagnosis in youth, as well as family and provider satisfaction.

The next steps include refinement of the current 4T study 1, developing a business case, and broader implementation of the 4T study. In study 2, we are including a more pragmatic cadence of remote data review and disseminating exercise education and activity tracking to both English- and Spanish-speaking families. The overall goal is to create and implement a translatable program that can facilitate better outcomes for pediatric clinics across the USA.
Inflammatory Myofibroblastic Tumor of the Placenta With Subsequent Successful Pregnancy and Benign Hysterectomy: A Case Report With 59-Month Follow-up
Authors: Schwartz Cooper , Gundogan Fusun , Singh Kamaljeet , Schoolmeester J. Kenneth , Banet Natalie
Published: July 2022

Inflammatory myofibroblastic tumors (IMT) are rare neoplasms of intermediate malignant potential which have been described in the gynecologic tract, predominantly in the myometrial wall, but also in association with the placenta. Like those in other organs, IMT of the placenta are characterized by molecular abnormalities, most commonly anaplastic lymphoma kinase gene rearrangements, and are often positive for anaplastic lymphoma kinase immunohistochemically. Although the clinical behavior of placental IMTs has so far proven benign, a successful intrauterine pregnancy with subsequent negative hysterectomy following a placental IMT has not been documented. Herein is presented a case of a 27-yr-old noted to have a 2 cm IMT of the extraplacental membranes at delivery, after which the patient received no further treatment. After 56 mo, the patient experienced a subsequent normal delivery in a pregnancy complicated by gestational diabetes. No longer desiring fertility, the patient elected to have a hysterectomy to confirm the absence of IMT at 59 mo and the uterus was unremarkable. This case provides insight into possible outcomes for patients with a rare tumor who may desire future fertility and may otherwise be advised to undergo hysterectomy in the setting of an unclear clinical course.
An Unusual Benign Uterine Stromal Spindle Cell Tumor Harboring JAZF1::BCORL1
Authors: Rodriguez Pena Maria D.C. , Mubeen Aysha , Harada Shuko , Prieto Granada Carlos N.
Published: July 2022

Uterine mesenchymal lesions demonstrate various underlying genomic alterations involving MED12, JAZF1, YWHAE, BCOR, and ALK genes, among others. Recent publications describe a subset of high-grade endometrial stromal sarcoma lesions harboring BCORL1 gene aberrations including JAZF1::BCORL1. Herein, we present an unusual benign endomyometrial spindle cell lesion that defies classificatory efforts by demonstrating mixed histomorphologic and immunohistochemical features of endometrial stromal nodule, leiomyoma, and uterine inflammatory myofibroblastic tumor while harboring a JAZF1::BCORL1. The lesion was found in a 43-yr-old woman with pelvic pain and heavy menses as a 5.5 cm well-circumscribed ulcerated mass fungating from the cervical os. Microscopic examination revealed a polypoid, well-circumscribed, moderately cellular endomyometrial tumor composed by bland spindle cells haphazardly disposed within a slightly edematous stroma enriched by a delicate network of thin-walled vessels that were occasionally encircled by the tumor cells. Unequivocal evidence of tongue-like growth pattern into the myometrium, tumor-type necrosis or increased mitotic activity was not identified after sampling the entire lesion. The lesion showed patchy immunoreactivity for both smooth muscle actin-alpha and desmin while negative for CD10, HMB45, ALK (D5F3), and BCOR. An Archer FusionPlex panel assay demonstrated a fusion involving both exons 4 from the JAZF1 and BCORL1 genes. The JAZF1::BCORL1 has not, to the best of our knowledge, been previously reported in a benign/low-grade mesenchymal uterine lesion.
Collision Tumor of the Ovary Involving Sertoli-Leydig Cell Tumor and High-Grade Serous Carcinoma—Report of the First Case
Authors: Omo-Ogboi Allen C. , Deavers Michael T. , Schmeler Kathleen M. , Tandon Nidhi
Published: July 2022

We report a collision tumor in the ovary of a 60-yr-old woman composed of high-grade serous carcinoma and Sertoli-Leydig cell tumor. Collision tumors in the ovary are rare and to the best of our knowledge, combination of ovarian high-grade serous carcinoma and Sertoli-Leydig cell tumor has not been described before.
The Duration and Magnitude of Postdischarge Venous Thromboembolism Following Colectomy
Authors: Lewis-Lloyd Christopher A. , Humes David J. , West Joe , Peacock Oliver , Crooks Colin J.
Published: July 2022

Objective:

To assess the impact of current guidelines by reporting weekly postoperative postdischarge venous thromboembolism (VTE) rates.

Summary Background Data:

Disparity exists between the postoperative thromboprophylaxis duration colectomy patients receive based on surgical indication, where malignant resections routinely receive 28 days extended thromboprophylaxis into the postdischarge period and benign resections do not.

Methods:

English national cohort study of colectomy patients between 2010 and 2019 using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care data. Stratified by admission type and surgical indication, absolute incidence rates (IRs) per 1000 person-years and adjusted incidence rate ratios (aIRRs) for postdischarge VTE were calculated for the first 4 weeks following resection and postdischarge VTE IRs for each postoperative week to 12 weeks postoperative.

Results:

Of 104,744 patients, 663 (0.63%) developed postdischarge VTE within 12 weeks after colectomy. Postdischarge VTE IRs per 1000 person-years for the first 4 weeks postoperative were low following elective resections [benign: 20.66, 95% confidence interval (CI): 13.73–31.08; malignant: 28.95, 95% CI: 23.09–36.31] and higher following emergency resections (benign: 47.31, 95% CI: 34.43–65.02; malignant: 107.18, 95% CI: 78.62–146.12). Compared with elective malignant resections, there was no difference in postdischarge VTE risk within 4 weeks following elective benign colectomy (aIRR=0.92, 95% CI: 0.56–1.50). However, postdischarge VTE risks within 4 weeks following emergency resections were significantly greater for benign (aIRR=1.89, 95% CI: 1.22–2.94) and malignant (aIRR=3.13, 95% CI: 2.06–4.76) indications compared with elective malignant colectomy.

Conclusions:

Postdischarge VTE risk within 4 weeks of colectomy is ∼2-fold greater following emergency benign compared with elective malignant resections, suggesting emergency benign colectomy patients may benefit from extended VTE prophylaxis.
A Telemedicine Alternative to the 6-Minute Walk Test Using Personal Activity Trackers in Liver Transplant Candidates
Authors: Duarte-Rojo Andres , Brown Rebecca A. , Bloomer Pamela M. , Nunez Duarte Marie , Grubbs Rachel K. , Hernaez Ruben
Published: July 2022

Background.

The COVID-19 pandemic has limited liver transplant (LT) candidates access to clinics. Telehealth methods to assess frailty are needed. We developed a method to estimate the step length of LT candidates, which would permit remotely obtaining the 6-min walk test (6MWT) distance with a personal activity tracker (PAT).

Methods.

6MWT was performed while candidates wore a PAT. On first 21 subjects (stride cohort), the step length was measured and compared with calculated one (6MWT-distance/6MWT steps). On a second cohort (PAT-6MWT; n = 116), we collected the 6MWT step count and used multivariable models to generate formulas estimating step length. We multiplied the estimated step length times 6MWT steps to estimate the distance and compared it to the measured distance. The liver frailty index (LFI) and 6MWT were used as frailty metrics.

Results.

Measured/calculated step length were highly correlated (ρ = 0.85; P < 0.001) in the stride cohort. In the PAT-6MWT cohort, LFI was the strongest variable associated with step length, along with height, albumin, and large-volume paracentesis (R
2 = 0.58). On a second model without LFI, age, height, albumin, hemoglobin, and large-volume paracentesis were strongly associated with step length (R
2 = 0.45). There was a robust correlation between observed 6MWT and PAT-6MWT utilizing step length equations with (ρ = 0.80; P < 0.001) or without LFI (ρ = 0.75; P < 0.001). Frailty by 6MWT <250 m did not change significantly using the observed (16%) or the with/without LFI-estimated (14%/12%) methods.

Conclusions.

We created a method to obtain 6MWT distance remotely with the use of a PAT. This novel approach opens the possibility of performing telemedicine PAT-6MWT to monitor LT candidates’ frailty status.
Alterations in Somatic Driver Genes Are Associated with Response to Neoadjuvant FOLFIRINOX in Patients with Localized Pancreatic Ductal Adenocarcinoma
Authors: Ecker Brett L , Court Colin M , Janssen Quisette P , Tao Alice J , D’Angelica Michael I , Drebin Jeffrey A , Gonen Mithat , O’Reilly Eileen M , Jarnagin William R , Wei Alice C ,   for the David M Rubenstein Center for Pancreatic Cancer Research Group at Memorial Sloan Kettering Cancer Center
Published: July 2022

BACKGROUND:

There is increased use of neoadjuvant fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers of treatment response.

STUDY DESIGN:

Consecutive patients (n = 196) with resectable, borderline resectable or locally advanced PDAC (2012–2019) receiving FOLFIRINOX as initial treatment and with targeted sequencing of a pretreatment biopsy were identified in a prospective institutional database. Genomic alterations were determined in the 4 driver mutations (KRAS, TP53, CDKN2A, SMAD4), and associations between genomic alterations and clinical outcomes were assessed.

RESULTS:

Alterations in KRAS (n = 172, 87.8%) and TP53 (n = 131, 66.8%) were common; alterations in CDKN2A (n = 49, 25.0%) and SMAD4 (n = 36, 18.4%) were less frequently observed. A total of 105 patients (53.6%) were able to undergo resection, of whom 8 (7.6%) had a complete/near-complete pathologic response. There were no somatic alterations associated with major pathologic response. Alterations in SMAD4 were associated with a lower rate of surgical resection (27.8% vs 59.4%, p < 0.001); this was additionally observed in a multivariable regression model accounting for resectability status (OR 0.35, 95% confidence interval [CI] 0.15–0.85). Thirty-three patients (16.8%) developed metastatic disease while on neoadjuvant therapy. SMAD4 alterations were associated with a significant risk of metastatic progression on therapy when controlling for resectability status (OR 3.31, 95% CI 1.44–7.60).

CONCLUSIONS:

SMAD4 alterations are associated with more frequent development of metastasis during neoadjuvant FOLFIRINOX and lower probability of reaching surgical resection. Evaluation of alternative chemotherapy regimens in patients with SMAD4 alterations will be important to distinguish whether this represents a prognostic or predictive biomarker.
Robotic Foregut Surgery in the Veterans Health Administration: Increasing Prevalence, Decreasing Operative Time, and Improving Outcomes
Authors: Napolitano Michael A , Zebley James A , Wagner Kelly , Holleran Timothy J , Werba Gregor , Sparks Andrew D , Trachiotis Gregory , Brody Fred
Published: July 2022

BACKGROUND:

Historically, robotic surgery incurs longer operative times, higher costs, and nonsuperior outcomes compared with laparoscopic surgery. However, in areas of limited visibility and decreased accessibility such as the gastroesophageal junction, robotic platforms may improve visualization and facilitate dissection. This study compares 30-day outcomes between robotic-assisted foregut surgery (RAF) and laparoscopic-assisted foregut surgery in the Veterans Health Administration.

STUDY DESIGN:

This is a retrospective review of the Veterans Affairs Quality Improvement Program database. Patients undergoing laparoscopic-assisted foregut surgery and RAF were identified using CPT codes 43280, 43281, 43282, and robotic modifier S2900. Multivariable logistic regression and multivariable generalized linear models were used to analyze the independent association between surgical approach and outcomes of interest.

RESULTS:

A total of 9,355 veterans underwent minimally invasive fundoplication from 2008 to 2019. RAF was used in 5,392 cases (57.6%): 1.63% of cases in 2008 to 83.41% of cases in 2019. After adjusting for confounding covariates, relative to laparoscopic-assisted foregut surgery, RAF was significantly associated with decreased adjusted odds of pulmonary complications (adjusted odds ratio [aOR] 0.44, p < 0.001), acute renal failure (aOR 0.14, p = 0.046), venous thromboembolism (aOR 0.44, p = 0.009) and increased odds of infectious complications (aOR 1.60, p = 0.017). RAF was associated with an adjusted mean ± SD of 29 ± 2–minute shorter operative time (332 minutes vs 361 minutes; p < 0.001).

CONCLUSIONS:

Veterans undergoing RAF ascertained shorter operative times and reduced complications vs laparoscopy. As surgeons use the robotic platform, clinical outcomes and operative times continue to improve, particularly in operations where extra articulation in confined spaces is required
Women Empowering Women: Assessing the American College of Surgeons Women in Surgery Committee Mentorship Program
Authors: Oppenheimer-Velez Marianna , Sims Carrie , Labiner Hanna , Baxter Nancy , Kozar Rosemary , McCoy Jacee , Sanfey Hilary , Litle Virginia , Klingensmith Mary , Pories Susan
Published: July 2022

BACKGROUND:

Mentorship is an important factor for career promotion and professional development. The Women in Surgery Committee developed a mentorship program that matched early career female surgeons to senior female surgeons for 1 year. We hypothesized participation in the program would empower junior surgeons by providing opportunities to network and hone skills necessary to attain their career goals.

METHODS:

Survey was sent 4 to 6 weeks after program completion. Statements about mentorship and value of the Women in Surgery Committee program were ranked on a 5-point Likert scale ranging from strongly disagree (1) to strongly agree (5). Participants were compared based on frequency of encounters using Student’s t-test.

RESULTS:

A total of 105 pairs were identified; response rate was 60%. Results reported as (mean ± SD). Participants believed mentorship was essential for young surgeons (4.5 ± 1.0), and limiting the program to female surgeons added value (4.4 ± 0.6). When compared with mentees who met less than 4 times in a year, those who met 4 or more times perceived the program as beneficial (4.4 ± 0.82, p < 0.001). Mentees who met 4 or more times in a year benefitted from creating and achieving goals (4.3 ± 0.75, p < 0.001), setting expectations (4.5 ± 0.6, p < 0.001), providing networking opportunities (4.1 ± 1.1, p < 0.05), and developing professional skills (3.9 ± 0.98).

Conclusion:

The Women in Surgery Committee Mentorship Program provides an opportunity for young female surgeons; however, perceived benefit is dependent on mentee engagement.
Chromosome 2q12.3-q13 copy number variants in patients with neurodevelopmental disorders: genotype-phenotype correlation and new hotspots
Authors: Aarabi Mahmoud , Baumann Jacqueline , Babcock Melanie , Kessler Elena , Sebastian Jessica , Madan-Khetarpal Suneeta , Hu Jie , Ou Zhishuo , Yatsenko Svetlana
Published: July 2022

Introduction

The complex structure of the chromosome 2q12.3-q13 region provides a high chance of recombination events between various low copy repeats (LCRs). Copy number variants (CNV) in this region are present in both healthy populations and individuals affected with developmental delay, autism and congenital anomalies. Variable expressivity, reduced penetrance and limited characterization of the affected genes have complicated the classification of the CNVs clinical significance.

Methods

Chromosomal microarray analysis data were reviewed for 10 298 patients with neurodevelopmental disorders referred to the UPMC Medical Genetics and Genomics Laboratories. A genotype-phenotype correlation was performed among the patients harboring the 2q12.3-q13 CNVs with overlapping genomic intervals.

Results

We identified 17 (1 in ~600) individuals with rare CNVs in the 2q12.3-q13 region, including nine patients with deletions, seven individuals with duplications and one patient who had both a deletion and a duplication. Likely pathogenic CNVs with the breakpoints between LCRs encompassing the potential dosage-sensitive genes BCL2L11, BUB1, FBLN7 and TMEM87B were the most common. CNVs were also observed between LCRs surrounding the RANBP2 and LIMS1 genes.

Conclusion:

Our study provides evidence for pathogenic CNV hotspots within the chromosome 2q12.3-q13 region. We suggest CNV classification based on the affected interval and the involvement of potential dosage-sensitive genes in these patients.
Vaccine, Booster and Natural Antibody Binding to SARS-CoV-2 Omicron (BA.1) Spike Protein and Vaccine Efficacy
Authors: James-Pemberton Philip H. , Helliwell Mark W. , Olkhov Rouslan V. , Kohli Shivali , Westlake Aaron C. , Farrar Benjamin M. , Sutton Ben J. , Ager Nicholas D. , Shaw Andrew M.
Published: July 2022

The SARS-CoV-2 Omicron variant (BA.1) has 25 unique mutations to the Spike glycoprotein, suggesting the efficacy of current vaccines against the new variant may be seriously degraded. A fully quantitative antibody binding study was performed for Spike Omicron (SO) and original Spike (S) proteins simultaneously on three cohorts of patients: convalescent following RT-PCR-confirmed infection in early 2020, double-vaccinated at ≥2 weeks, and vaccine boosters. The average (mode) of the booster cohort response distributions were 15.1 mg/L and 13.4 mg/L for S and SO, respectively, compared with the significantly lower double-vaccinated average, S=2.4 mg/L, SO=2.0 mg/L, and natural infections average S=2.0 mg/L, SO = 1.8 mg/L. A preliminary epitope degradation screen was performed for a panel of antibodies raised to the S1 and S2 regions of the original S protein. The panel showed significant degradation to antibody epitopes in the S1 region. Differential antibody binding of the vaccine response to S and SO suggests vaccine efficacy may be reduced by up to 50% against the Omicron variant.
A Multimodal Assessment of the Heterogeneous Nature of Post-mTBI Dizziness
Authors: Pelo Ryan , Gaudette Elle , Millsap Leah , Martindale Cecilia , Dibble Leland E. , Cortez Melissa M. , Fino Peter C.
Published: July 2022

Dizziness after mild traumatic brain injury (mTBI) is commonly attributed to impairment within the vestibular system. However, oculomotor, mobility, and autonomic dysfunction can also contribute to patient-reported dizziness. The purpose of this preliminary study was to examine whether a multimodal battery of assessments could help explain patient-reported dizziness after mTBI. Twenty-three participants with concussion-related symptoms completed the Dizziness Handicap Inventory (DHI) to evaluate burden imposed by dizziness on daily activities and a battery of tests designed to incorporate domains that have been shown to contribute to dizziness (e.g., vestibular, oculomotor, balance and mobility, and autonomic dysfunction). Specific outcomes included quantitative variables obtained from: Vestibular Ocular Motor Screening (VOMS); standing for 30 seconds with feet together, eyes closed, with hands on their hips on both firm and foam surfaces; walking for one minute at a comfortable pace; and a Head-up Tilt (HUT) Test. Univariate associations between DHI and individual measures were assessed, and a backwards-stepwise regression model determined the multi-variable association. There were no strong associations and only a few moderate associations between individual functional measure and DHI total score. A total of eight variables had univariate correlation coefficients larger than 0.20 in magnitude. The final model from the backwards-stepwise procedure explained 69% of the variance in DHI and retained only three variables: peak turning speed from the one-minute walk; mean blood pressure (MBP) during the HUT; and the total VOMS score. Isolated assessments of individual domains of function have weak-to-moderate associations with post-mTBI dizziness. Conversely, a multivariable model that contained measures of mobility, autonomic function, and symptomatic complaints to vestibular and ocular provocation explained 69% of the variance in dizziness. These results suggest that dizziness is physiologically heterogeneous in nature and support the use of multi-domain assessments in patients with dizziness after mTBI.
Thiol-mediated Uptake of a Cysteine-containing Nanobody for Anti-Cancer Drug Delivery
Authors: Goerdeler Felix , Reuber Emelie E. , Lühle Jost , Leichnitz Sabrina , Freitag Anika , Nedielkov Ruslan , Möller Heiko M. , Seeberger Peter H. , Moscovitz Oren
Published: July 2022

The identification of tumor-specific biomarkers is one of the bottlenecks in the development of cancer therapies. Previous work revealed altered surface levels of reduced/oxidized cysteines in many cancers due to overexpression of redox-controlling proteins such as protein disulfide isomerases on the cell surface. Alterations in surface thiols can promote cell adhesion and metastasis, making thiols attractive targets for treatment. Only a few tools are available to study surface thiols on cancer cells and exploit them for theranostics. Here, we describe a nanobody (CB2) that recognizes B cell lymphoma in a thiol-dependent manner. CB2 binding strictly requires the presence of a non-conserved cysteine in the antigen-binding region and correlates with elevated surface levels of free thiols on B cell lymphoma compared to healthy lymphocytes. Nanobody CB2 can induce complement-dependent cytotoxicity against lymphoma cells when functionalized with synthetic rhamnose trimers. Lymphoma cells internalize CB2 in a thiol-mediated manner such that the nanobody can be used to deliver cytotoxic agents. Hence, surface thiols can be used as lymphoma biomarkers and targeted by thiol-binding nanobodies. Functionalization of internalizable CB2 is the basis for a range of diagnostic and therapeutic applications of this thiol-binding nanobody.

TOC Graphic

Synopsis

Nanobody CB2 specifically binds and internalizes into B cell lymphoma via thiol-based interactions. Functionalized CB2 can be used for complement recruitment or drug delivery to lymphoma cells.
Single cell transcriptomics of Atlantic salmon (Salmo salar L.) liver reveals cellular heterogeneity and immunological responses to challenge by Aeromonas salmonicida
Authors: Taylor Richard S , Ruiz Daniels Rose , Dobie Ross , Naseer Shahmir , Clark Thomas C , Henderson Neil C , Boudinot Pierre , Martin Sam AM , Macqueen Daniel J
Published: July 2022

The liver is a multitasking organ with essential functions for vertebrate health spanning metabolism and immunity. In contrast to mammals, our understanding of liver cellular heterogeneity and its role in regulating immunological status remains poorly defined in fishes. Addressing this knowledge gap, we generated a transcriptomic atlas of 47,432 nuclei isolated from the liver of Atlantic salmon (Salmo salar L.) contrasting control fish with those challenged with a pathogenic strain of Aeromonas salmonicida, a problematic bacterial pathogen in global aquaculture. We identified the major liver cell types and their sub-populations, revealing poor conservation of many hepatic cell marker genes utilized in mammals, while identifying novel heterogeneity within the hepatocyte, lymphoid, and myeloid lineages. This included polyploid hepatocytes, multiple T cell populations including γδ T cells, and candidate populations of monocytes/macrophages/dendritic cells. A dominant hepatocyte population radically remodeled its transcriptome following infection to activate the acute phase response and other defense functions, while repressing routine functions such as metabolism. These defense-specialized hepatocytes showed strong activation of genes controlling protein synthesis and secretion, presumably to support the release of acute phase proteins into circulation. The infection response further involved up-regulation of numerous genes in an immune-cell specific manner, reflecting functions in pathogen recognition and killing, antigen presentation, phagocytosis, regulation of inflammation, B cell differentiation and T cell activation. Overall, this study greatly enhances our understanding of the multifaceted role played by liver cells in immune defense and metabolic remodeling following infection and provides many novel cell-specific marker genes to empower future studies of this organ in fishes.
Criticality of neuronal avalanches in human sleep and their relationship with sleep macro- and micro-architecture
Authors: Scarpetta Silvia , Morrisi Niccolò , Mutti Carlotta , Azzi Nicoletta , Trippi Irene , Ciliento Rosario , Apicella Ilenia , Messuti Giovanni , Angiolelli Marianna , Lombardi Fabrizio , Parrino Liborio , Vaudano Anna Elisabetta
Published: July 2022

Sleep plays a key role in preserving brain function, keeping the brain network in a state that ensures optimal computational capabilities. Empirical evidence indicates that such a state is consistent with criticality, where scale-free neuronal avalanches emerge. However, the relationship between sleep, emergent avalanches, and criticality remains poorly understood. Here we fully characterize the critical behavior of avalanches during sleep, and study their relationship with the sleep macro- and micro-architecture, in particular the cyclic alternating pattern (CAP). We show that avalanche size and duration distributions exhibit robust power laws with exponents approximately equal to −3/2 e −2, respectively. Importantly, we find that sizes scale as a power law of the durations, and that all critical exponents for neuronal avalanches obey robust scaling relations, which are consistent with the mean-field directed percolation universality class. Our analysis demonstrates that avalanche dynamics depends on the position within the NREM-REM cycles, with the avalanche density increasing in the descending phases and decreasing in the ascending phases of sleep cycles. Moreover, we show that, within NREM sleep, avalanche occurrence correlates with CAP activation phases, particularly A1, which are the expression of slow wave sleep propensity and have been proposed to be beneficial for cognitive processes. The results suggest that neuronal avalanches, and thus tuning to criticality, actively contribute to sleep development and play a role in preserving network function. Such findings, alongside characterization of the universality class for avalanches, open new avenues to the investigation of functional role of criticality during sleep with potential clinical application.

Significance statement

We fully characterize the critical behavior of neuronal avalanches during sleep, and show that avalanches follow precise scaling laws that are consistent with the mean-field directed percolation universality class. The analysis provides first evidence of a functional relationship between avalanche occurrence, slow-wave sleep dynamics, sleep stage transitions and occurrence of CAP phase A during NREM sleep. Because CAP is considered one of the major guardians of NREM sleep that allows the brain to dynamically react to external perturbation and contributes to the cognitive consolidation processes occurring in sleep, our observations suggest that neuronal avalanches at criticality are associated with flexible response to external inputs and to cognitive processes, a key assumption of the critical brain hypothesis.
Asymmetric learning of dynamic spatial regularities in visual search: facilitation of anticipated target locations, no suppression of predictable distractor locations
Authors: Yu Hao , Allenmark Fredrik , Müller Hermann J. , Shi Zhuanghua
Published: July 2022

Static statistical regularities in the placement of targets and salient distractors within the search display can be learned and used to optimize attentional guidance. Whether statistical learning also extends to dynamic regularities governing the placement of targets and distractors on successive trials has been less investigated. Here, we applied the same dynamic cross-trial regularity (one-step shift of the critical item in clock-/counterclockwise direction) either to the target or a distractor, and additionally varied whether the distractor was defined in a different (color) or the same dimension (shape) as the target. We found robust learning of the predicted target location: processing of the target at this (vs. a random) location was facilitated. But we found no evidence of proactive suppression of the predictable distractor location. Facilitation of the anticipated target location was associated with explicit awareness of the dynamic regularity, whereas participants showed no awareness of the distractor regularity. We propose that this asymmetry arises because, owing to the target’s central role in the task set, its location is explicitly encoded in working memory, enabling the learning of dynamic regularities. In contrast, the distractor is not explicitly encoded; so, statistical learning of distractor locations is limited to static regularities.

Public significance statement

Can we learn the cross-trial dynamic regularity of a target or a task-irrelevant salient distractor (e.g., one-step shift of the critical item in clock-/counterclockwise direction) to boost search performance? The present study found robust learning of the predicted target location, but no evidence of proactive suppression of the predictable distractor location. Facilitation of the anticipated target location was associated with explicit awareness of the dynamic regularity. This asymmetry highlights the important role of the target-centered task set in the learning of dynamic regularities.
Reference compounds for characterizing cellular injury in high-content cellular morphology assays
Authors: Dahlin Jayme L. , Hua Bruce K. , Zucconi Beth E. , Nelson Shawn D. , Singh Shantanu , Carpenter Anne E. , Shrimp Jonathan H. , Lima-Fernandes Evelyne , Wawer Mathias J. , Chung Lawrence P.W. , Agrawal Ayushi , O’Reilly Mary , Barsyte-Lovejoy Dalia , Szewczyk Magdalena , Li Fengling , Lak Parnian , Cuellar Matthew , Cole Philip A. , Meier Jordan L. , Thomas Tim , Baell Jonathan B. , Brown Peter J. , Walters Michael A. , Clemons Paul A. , Schreiber Stuart L. , Wagner Bridget K.
Published: July 2022

Robust, generalizable approaches to identify compounds efficiently with undesirable mechanisms of action in complex cellular assays remain elusive. Such a process would be useful for hit triage during high-throughput screening and, ultimately, predictive toxicology during drug development. We generated cell painting and cellular health profiles for 218 prototypical cytotoxic and nuisance compounds in U-2 OS cells in a concentration-response format. A diversity of compounds causing cellular damage produced bioactive cell painting morphologies, including cytoskeletal poisons, genotoxins, nonspecific electrophiles, and redox-active compounds. Further, we show that lower quality lysine acetyltransferase inhibitors and nonspecific electrophiles can be distinguished from more selective counterparts. We propose that the purposeful inclusion of cytotoxic and nuisance reference compounds such as those profiled in this Resource will help with assay optimization and compound prioritization in complex cellular assays like cell painting.
White matter microstructural abnormality precedes cortical volumetric decline in Alzheimer’s disease: evidence from data-driven disease progression modelling
Authors: Parker CS , Weston PSJ , Zhang H , Oxtoby NP ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: July 2022

Sequencing the regional progression of neurodegeneration in Alzheimer’s disease (AD) informs disease mechanisms and facilitates identification and staging of individuals at greatest risk of imminent cognitive decline, which may aid the development of early therapeutic interventions. Previous attempts to sequence neurodegeneration have analysed measures of regional volume and identified the initial sites of atrophy. However, focal microstructural alterations in white matter have also been reported in early AD. Yet, the temporal ordering of abnormality in measures of white matter microstructure relative to grey matter volume has not been established. In this study we used event-based modelling of disease progression (EBM) to provide a data-driven evaluation of the temporal sequence of abnormality in markers of white matter microstructure relative to grey matter volume. Regional microstructural metrics derived from diffusion tensor imaging (DTI) and regional volumes from Freesurfer cortical parcellation were obtained from the Alzheimer’s disease Neuroimaging Initiative (ADNI) database for 441 amyloid-positive participants (81 AD-dementia, 159 mild cognitive impairment, 201 cognitively normal). The estimated sequence shows a series of abnormalities in markers of white matter microstructure, followed by sequential grey matter volumetric decline, with no overlap between the two. Analysis of positional variance and cross-validation supports the robustness of our findings. These results provide the first data-driven evidence that markers of white matter microstructural degeneration precede those of cortical volumetric decline in the AD cascade. This prompts a re-evaluation of the view that regional volumetric decline can be used to characterise the very earliest stages of AD neurodegeneration. Instead, we suggest that white matter microstructural markers provide an earlier window into AD neurodegeneration. An early staging system of AD neurodegeneration based on measures of brain microstructure may find application in selecting AD subjects with early but minimal brain damage for clinical trials that aim to prevent cognitive decline.
Integrative genome-scale analyses reveal post-transcriptional signatures of early human small intestinal development in a directed differentiation organoid model
Authors: Hung Yu-Han , Capeling Meghan , Villanueva Jonathan W. , Kanke Matt , Shanahan Michael T. , Huang Sha , Cubitt Rebecca L. , Rinaldi Vera D. , Schimenti John C. , Spence Jason R. , Sethupathy Praveen
Published: July 2022

MicroRNAs (miRNAs) are important post-transcriptional gene regulators in organ development. To explore candidate roles for miRNAs in prenatal SI lineage specification in humans, we used a multi-omic analysis strategy in a directed differentiation model that programs human pluripotent stem cells toward the SI lineage. We leveraged small RNA-seq to define the changing miRNA landscape, and integrated chromatin run-on sequencing (ChRO-seq) and RNA-seq to define genes subject to significant post-transcriptional regulation across the different stages of differentiation. Our analyses showed that the elevation of miR-182 and reduction of miR-375 are key events during SI lineage specification. We demonstrated that loss of miR-182 leads to an increase in the foregut marker SOX2. We also used single-cell analyses in murine adult intestinal crypts to support a life-long role for miR-375 in the regulation of Zfp36l2. Finally, we uncovered opposing roles of SMAD4 and WNT signaling in regulating miR-375 expression during SI lineage specification. Beyond the mechanisms highlighted in this study, we also present a web-based application for exploration of post-transcriptional regulation and miRNA-mediated control in the context of early human SI development.

Graphical Abstract