Local Disordered Region Sampling (LDRS) for ensemble modeling of proteins with experimentally undetermined or low confidence prediction segments.

Summary: The Local Disordered Region Sampling (LDRS, pronounced loaders) tool is a new module developed for IDPConformerGenerator, a previously validated approach to model intrinsically disordered proteins (IDPs). The IDPConformerGenerator LDRS module provides a method for generating all-atom conformations of intrinsically disordered protein regions at N- and C-termini of and in loops or linkers between folded regions of an existing protein structure. These disordered elements often lead to missing coordinates in experimental structures or low confidence in predicted structures.

Delineating Structural Propensities of the 4E-BP2 Protein via Integrative Modeling and Clustering.

The intrinsically disordered 4E-BP2 protein regulates mRNA cap-dependent translation through interaction with the predominantly folded eukaryotic initiation factor 4E (eIF4E). Phosphorylation of 4E-BP2 dramatically reduces the level of eIF4E binding, in part by stabilizing a binding-incompatible folded domain. Here, we used a Rosetta-based sampling algorithm optimized for IDRs to generate initial ensembles for two phospho forms of 4E-BP2, non- and 5-fold phosphorylated (NP and 5P, respectively), with the 5P folded domain flanked by N- and C-terminal IDRs (N-IDR and C-IDR, respectively).

Local Disordered Region Sampling (LDRS) for Ensemble Modeling of Proteins with Experimentally Undetermined or Low Confidence Prediction Segments.

The Local Disordered Region Sampling (LDRS, pronounced ) tool, developed for the IDPConformerGenerator platform (Teixeira 2022), provides a method for generating all-atom conformations of intrinsically disordered regions (IDRs) at N- and C-termini of and in loops or linkers between folded regions of an existing protein structure. These disordered elements often lead to missing coordinates in experimental structures or low confidence in predicted structures. Requiring only a pre-existing PDB structure of the protein with missing coordinates or with predicted confidence scores and its full-length primary sequence, LDRS will automatically generate physically meaningful conformational ensembles of the missing flexible regions to complete the full-length protein.

Multisite phosphorylation and binding alter conformational dynamics of the 4E-BP2 protein.

Intrinsically disordered proteins (IDPs) play critical roles in regulatory protein interactions, but detailed structural/dynamic characterization of their ensembles remain challenging, both in isolation and when they form dynamic "fuzzy" complexes. Such is the case for mRNA cap-dependent translation initiation, which is regulated by the interaction of the predominantly folded eukaryotic initiation factor 4E (eIF4E) with the intrinsically disordered eIF4E binding proteins (4E-BPs) in a phosphorylation-dependent manner. Single-molecule Förster resonance energy transfer showed that the conformational changes of 4E-BP2 induced by binding to eIF4E are non-uniform along the sequence; while a central region containing both motifs that bind to eIF4E expands and becomes stiffer, the C-terminal region is less affected.

Impact of Cavity Shave Margins on Margin Status in Patients with Pure Ductal Carcinoma In Situ.

Background: We examined the impact of cavity shave margins (CSMs) on margin status in patients with pure ductal carcinoma in situ (DCIS) undergoing partial mastectomy (PM).

Methods: One hundred and nine patients from 2 multicenter, randomized controlled trials were identified with pure DCIS (no invasive cancer). Surgeons performed their best PM, with specimen radiography and resection of selective margins per surgeon discretion.

Nipple-sparing mastectomy: A review of outcomes at a single institution.

Nipple-sparing mastectomy (NSM) offers patients who are not candidates for breast-conserving treatment an aesthetically pleasing alternative to traditional mastectomy. Some studies have demonstrated its oncologic safety while others have demonstrated residual occult tumor cells at the nipple-areolar complex (NAC). These data prompt further review of oncologic outcomes after NSM.

Is radial scar on core needle biopsy a risk factor for malignancy? A single-center retrospective review and implications for management.

Introduction: Reported upgrade rate to malignancy of radial scars (RS) ranges widely (0%-40%) making management controversial.

Methods: A retrospective chart review was performed on patients with RS on core needle biopsy (CNB). Upgrade rates to malignancy and atypia on surgical excision were evaluated.

Prognostic value of HER2 status on circulating tumor cells in advanced-stage breast cancer patients with HER2-negative tumors.

Purpose: Discordance between HER2 expression in tumor tissue (tHER2) and HER2 status on circulating tumor cells (cHER2) has been reported. It remains largely underexplored whether patients with tHER2/cHER2 can benefit from anti-HER2 targeted therapies.

Methods: cHER2 status was determined in 105 advanced-stage patients with tHER2 breast tumors.

Resection of Cavity Shave Margins in Stage 0-III Breast Cancer Patients Undergoing Breast Conserving Surgery: A Prospective Multicenter Randomized Controlled Trial.

Objective: Single-center studies have demonstrated that resection of cavity shave margins (CSM) halves the rate of positive margins and re-excision in breast cancer patients undergoing partial mastectomy (PM). We sought to determine if these findings were externally generalizable across practice settings.

Methods: In this multicenter randomized controlled trial occurring in 9 centers across the United States, stage 0-III breast cancer patients undergoing PM were randomly assigned to either have resection of CSM ("shave" group) or not ("no shave" group).

Association of clinical outcomes in metastatic breast cancer patients with circulating tumour cell and circulating cell-free DNA.

Background: Both circulating tumour cell (CTC) and total circulating cell-free DNA (ccfDNA) predict cancer patient prognosis. However, no study has explored the prognostic value of the combined use of CTC and ccfDNA. We aimed to investigate individual and joint effects of CTC and ccfDNA on clinical outcomes of metastatic breast cancer (MBC) patients.

Do All Positive Margins in Breast Cancer Patients Undergoing a Partial Mastectomy Need to Be Resected?

Background: Positive margins have been reported in 20% to 40% of patients undergoing a partial mastectomy, often resulting in re-excision. How often the re-excision yields additional cancer and whether there are predictors of residual disease remain unknown.

Study Design: Patients who had a positive margin (defined as tumor at ink for patients with invasive disease or within 1 mm for patients with ductal carcinoma in situ) in the SHAVE (A Randomized Controlled Trial of Routine Shave Margins Versus Standard Partial Mastectomy in Breast Cancer Patients) trial before randomization were evaluated to determine the rate of additional disease either in cavity shave margins or at re-excision.

Quality-of-Life Outcomes Improve with Nipple-Sparing Mastectomy and Breast Reconstruction.

Background: Loss of the nipple-areola complex can be psychologically and sexually devastating. Nipple-sparing mastectomy provides robust cosmetic results, but few studies have investigated the quality-of-life outcomes associated with it.

Methods: The authors performed an institutional review board-approved retrospective study of 32 patients who underwent nipple-sparing mastectomy with implant-based or autologous reconstruction and 32 control patients who underwent non-nipple-sparing mastectomy with reconstruction matched by reconstruction type and operative period.

Clinical-pathological features and treatment modalities associated with recurrence in DCIS and micro-invasive carcinoma: Who to treat more and who to treat less.

The primary aim in the management of DCIS is the prevention of recurrence and contralateral tumor. Risk factors for DCIS recurrence and appropriate treatments are still widely debated. Adjuvant therapies after surgical resection reduce recurrences and contralateral disease, but these treatments have significant financial costs, side effects and there is a group of low-risk patients who would not gain additional benefit.

Reflex Estrogen Receptor (ER) and Progesterone Receptor (PR) Analysis of Ductal Carcinoma In Situ (DCIS) in Breast Needle Core Biopsy Specimens: An Unnecessary Exercise That Costs the United States $35 Million/y.

Most institutions reflexively test all breast core needle biopsy specimens showing ductal carcinoma in situ (DCIS) for estrogen receptor (ER) and progesterone receptor (PR). However, 5 factors suggest that this reflex testing unnecessarily increases costs. First, ER/PR results do not currently impact the next step in standard therapy; namely, surgical excision.

Economic Impact of Routine Cavity Margins Versus Standard Partial Mastectomy in Breast Cancer Patients: Results of a Randomized Controlled Trial.

Objective: The aim of the study was to compare costs associated with excision of routine cavity shave margins (CSM) versus standard partial mastectomy (PM) in patients with breast cancer.

Background: Excision of CSM reduces re-excision rates by more than 50%. The economic implications of this is, however, unclear.

Intraductal Papilloma with Benign Pathology on Breast Core Biopsy: To Excise or Not?

Background: The management of intraductal papillomas on core biopsy continues to be controversial. Papillomas with atypia are typically excised. However, it is unclear whether surgical excision is warranted for benign lesions.

A Randomized, Controlled Trial of Cavity Shave Margins in Breast Cancer.

Background: Routine resection of cavity shave margins (additional tissue circumferentially around the cavity left by partial mastectomy) may reduce the rates of positive margins (margins positive for tumor) and reexcision among patients undergoing partial mastectomy for breast cancer.

Methods: In this randomized, controlled trial, we assigned, in a 1:1 ratio, 235 patients with breast cancer of stage 0 to III who were undergoing partial mastectomy, with or without resection of selective margins, to have further cavity shave margins resected (shave group) or not to have further cavity shave margins resected (no-shave group). Randomization occurred intraoperatively after surgeons had completed standard partial mastectomy.

Reflex estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 (ER/PR/Her2) analysis of breast cancers in needle core biopsy specimens dramatically increases health care costs.

ER/PR/Her2 are often reflexively assessed in all core needle biopsies (CNBXs) containing invasive mammary carcinoma (IMC) so that neoadjuvant therapy can be considered. ER/PR/Her2 can be heterogenous, and there is growing consensus that negative results for any of these markers in small CNBXs should be repeated in larger excision specimens (EXS). The frequency and added cost of repeat testing of EXS containing untreated IMC with negative ER/PR/Her2 CNBX results has not previously been studied.

Frozen section evaluation of breast carcinoma sentinel lymph nodes: a retrospective review of 1,940 cases.

Many sentinel lymph node biopsies (SLNBs) are evaluated intraoperatively by frozen section, which may impact the need for further axillary dissection (AD). However, the need for AD in patients with small metastases has been recently called into question, meaning that frozen SLNB may be unnecessary. Furthermore, frozen section can compromise tissue for further study.

The number of lymph nodes dissected in breast cancer patients influences the accuracy of prognosis.

Background: Recent trials have suggested that axillary node dissection may not be warranted in some breast cancer patients with one to two positive nodes. Given that lymph node ratio (LNR; number of positive lymph nodes divided by the total examined) has been shown to be a significant prognostic factor, we sought to determine whether the number of nodes removed in this low risk population predicted survival.

Methods: The National Cancer Database is a comprehensive clinical surveillance resource capturing 70% of newly diagnosed malignancies in the United States; 309,216 breast cancer patients diagnosed between 1998 and 2005, with tumors ≤5 cm and one to two positive nodes, formed the cohort of interest.

Is there a correlation between breast cancer molecular subtype using receptors as surrogates and mammographic appearance?

Background: The identification of distinct molecular subtypes has changed breast cancer management. The correlation between mammographic appearance and molecular subtype for invasive breast cancer has not been extensively studied.

Methods: A retrospective review of our prospectively collected database was performed to evaluate the mammographic appearance and molecular subtypes of all cases of invasive breast cancers diagnosed between 2003 and 2010.

Biomarker modulation following short-term vorinostat in women with newly diagnosed primary breast cancer.

Purpose: Agents that target the epigenome show activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell-cycle arrest, apoptosis, and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly diagnosed invasive disease who received vorinostat and those who did not.

Does time to definitive treatment matter in patients with ductal carcinoma in situ?

Little is known about factors influencing time between diagnosis and definitive treatment in patients with ductal carcinoma in situ (DCIS). We sought to determine the factors influencing this delay time and implications on outcome. A retrospective review was performed of 127 patients with DCIS who were treated with definitive surgical excision at an academic center from 2000 to 2003.