bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rescuing off-equilibrium simulation data through dynamic experimental data with dynAMMo
Authors: Kolloff Christopher , Olsson Simon 
Published: November 2023

Abstract
Long-timescale behavior of proteins is fundamental to many biological processes. Molecular dynamics (MD) simulations and biophysical experiments are often used to study protein dynamics. However, high computational demands of MD limit what timescales are feasible to study, often missing rare events, which are critical to explain experiments. On the other hand, experiments are limited by low resolution. We present dynamic augmented Markov models (dynAMMo) to bridge the gap between these data and overcome their respective limitations. For the first time, dynAMMo enables the construction of mechanistic models of slow exchange processes that have been not observed in MD data by integrating dynamic experimental observables. As a consequence, dynAMMo allows us to bypass costly and extensive simulations, yet providing mechanistic insights of the system. Validated with controlled model systems and a well-studied protein, dynAMMo offers a new approach to quantitatively model protein dynamics on long timescales in an unprecedented manner.
Deposition of Sevelamer crystals in gastrointestinal tract and lung parenchyma: A rare autopsy finding
Authors: Liu J , Zaidi A , Sonawane S S , Guzman G , Qazi O 
Published: November 2023

Abstract

Introduction/Objective
Sevelamer carbonate is a non-calcium-based phosphate binder used for the management of hyperphosphatemia in patients with end stage renal disease. The well-known side effects of sevelamer include nausea, vomiting and abdominal pain. However, there are few case reports which described the deposition of sevelamer crystals in the gastrointestinal tract causing mucosal injury, pseudotumor or obstruction.

Methods/Case Report
We hereby present a case of a 43-year-old decedent female with past medical history of seizures, hypertension, cocaine use, type B aortic dissection status post thoracic endovascular aortic repair, total arch replacement, reconstruction of innominate, carotid, and subclavian artery who presented with hematochezia concerning for possible aorto-esophageal fistula on 10/06/2022 and acute kidney injury. Imaging showed a thrombus in mid-esophagus, blood in trachea and narrowing of the left main stem bronchus. Labs revealed worsening of BUN and creatinine and up trending hyperphosphatemia and therefore sevelamer carbonate via nasogastric route was started on 10/13/22.
Unfortunately, the patient’s hospital course was complicated, and she passed away on 11/14/2022. At autopsy, the deceased had gross evidence of acute lung injury with diffuse alveolar hemorrhage, aorta-bronchial ruptured aneurysm defect and aorto-esophageal fistulas. On histopathological examination, the stomach, small and large bowel showed autolysis, necrosis, and numerous rectangular shaped, non-polarizable crystals. The crystals with characteristic morphology of “fish scale” with hues of pink in the center and yellow to orange in the periphery were identified as sevelamer crystals. Interestingly, crystal deposition was also identified in lung parenchyma and rarely in aortic wall and the fistula.

Results (if a Case Study enter NA)
NA

Conclusion
As one of the more commonly used resins in end stage kidney disease, gastrointestinal adverse effect of sevelamer carbonate is often underrecognized. Our case report heightens the awareness of the characteristic morphology of this biologically inert agent, sevelamer to those who are unaware of their morphology. This case also highlights the adverse effect of sevelamer in all patients presenting with gastrointestinal symptoms, such as gastrointestinal bleeding and abdominal pain with the use of sevelamer.
HER2 amplification in cases with low HER2 expression by immunohistochemistry (IHC): A Single Institutional Experience
Authors: Podany P , Golastani R , Zhan H , Liang Y , Harigopal M , Krishnamurti U 
Published: November 2023

Abstract

Introduction/Objective
HER2 testing in invasive breast carcinoma (IBC) is the standard of care to determine patient eligibility for HER2 directed therapy with trasuzumab. Initial testing of tissue by HER2 immunohistochemistry (IHC) can be positive, negative, or equivocal. In equivocal cases as well as negative cases in our institution HER2 FISH is also performed. According to ASCO/CAP guidelines a subset of equivocal and negative IHC cases are considered HER2 positive if they meet criteria for increased HER2/CEP17 ratio and HER2 copy number by FISH, allowing more patients to be treated with HER2 directed therapies. HER2 grouping per ASCO is as follows; Group 1: HER2 copy number ≥4 signals/cell, Group 2: &lt;4.0 signals/cell, Group 3: ≥6 signals/cell, Group 4: HER2 copy number ≥4 and &lt;6 signals/cell, Group 5: HER2 copy number &lt;4 signals/cell

Methods/Case Report
All cases of IBC resection with HER2 IHC and FISH results from Jan 2018-Dec 2021 were included in this study. All cases positive for HER2 by IHC alone (3+ staining) were excluded. The ASCO/CAP 2018 guidelines for HER2 testing in breast cancer were used to evaluate HER2 positivity by FISH and the relation to IHC scores

Results (if a Case Study enter NA)
A total of 2630 IBC cases with both HER2 IHC and FISH testing were included. Of these, 131 (5.0%) were in FISH group 1, 17 (0.7%) in group 2, 11 (0.4%) in group 3, 161 (6.1%) in group 4, and 2310 (87.8%) in group 5. A total of 142 (5.4%) cases that were HER2 equivocal or negative by IHC were HER2 positive by FISH. Specifically, 0.3% of cases with an IHC score of 0, 1.4% with a score of 1+, and 14.6% of cases with a score of 2+ were positive by FISH. Of the 14.6% IHC 2+ cases that were FISH positive 13.3% were in FISH group 1 (115 cases) and 1.3% (11 cases) in FISH group 3. Of FISH positive cases 1.4% had an IHC score of 0, 9.9% had an IHC score of 1 and 88.7% had a score of 2

Conclusion
At our institution 14.6% of IBC with equivocal HER2 staining on IHC, 1.4% of cases with negative (1+) staining and 0.3% of cases with negative (0) were HER2 FISH positive. Since HER2 FISH is not reflexively performed on cases HER2 negative by IHC, this additional 1.7% will qualify for HER2 targeted therapy
Interpretation of low HER2 expression by IHC by traditional IHC assay may miss a small percentage of cases eligible for HER2 directed therapy. Accurate interpretation of HER2 low by IHC is critical as recent clinical trials have shown that low HER2 expression with IHC scores of 1+ or 2+ without gene amplification by FISH could benefit from Trastuzumab Deruxtecan
Comparison of FDA-Approved vs. Mayo Clinic’s Ki-67 Immunostaining Protocols for Breast Cancer Specimens: A Quantitative Analysis Using Artificial Intelligence (AI) Based Image Analysis Algorithms
Authors: Stoy L , del Rosario K , Plagge A , Lewis K , Yasir S , Chen Z 
Published: November 2023

Abstract

Introduction/Objective
Ki-67, a nuclear protein present during the active phases of the cell cycle, is an important prognostic and predictive marker for many tumor types, including breast cancer. This study compared the results of breast cancer specimens immunohistochemically (IHC) stained with the FDA-approved vs. Mayo Clinic’s (MC) validated Ki-67 protocol using AI-based image analysis algorithms for quantitative examination at an individual cell level.

Methods/Case Report
Sixty-two breast cancer specimens were selected with a rough equal representation of Ki-67 percentage in low (&lt;10%), intermediate (10-20%) and high (&gt;20%) categories. Two adjacent sections of each specimen were stained with the FDA and MC protocols, respectively, and scanned to obtain whole slide digital images. Two AI algorithms, one with tumor cell identification and the other without, were used to quantify positive and negative cells and calculate Ki-67 percentages.

Results (if a Case Study enter NA)
Both algorithms show high concordance between the two staining protocols, with r-squared scores of 0.989 and 0.992, respectively, analyzing with or without tumor identification. AI identified tumor better on MC stained slides vs. FDA stained slides. The results demonstrate a high-performance concordance between the MC and the FDA IHC staining protocols.

Conclusion
The data also illustrates the accuracy of using AI image analysis algorithms to compare different IHC protocols at an individual cell level. The AI tumor identification difference in slides stained with two IHC protocols reflects the importance of training an algorithm with a specific staining protocol to achieve optimal tumor recognition.
Invasive Paget disease of the breast: two unique cases with diagnostic conundrum
Authors: Shirai S , Saluja K , Zhang S , Guo T 
Published: November 2023

Abstract

Introduction/Objective
Invasive Paget disease of the breast is a rare entity with diagnostic challenges. It has been reported in 4-8% of cases of mammary Paget disease, while Paget disease itself represents only 1-4% of all breast carcinomas. The pigmented variant of this entity brings even greater diagnostic challenge. Herein, we present two patients with Paget disease of the breast with dermal invasion, one case with associated ulceration and another with pigmentation.

Methods/Case Report
Patient 1 is a 47-year-old female with a 9 mm right breast mass with a lobulated margins and calcifications. Simple mastectomy was grossly notable for nipple ulceration. Patient 2 is a 54-year-old female with a cm irregular mass in the right breast. Grossly, the nipple appeared blackened and mildly everted.

Results (if a Case Study enter NA)
Histopathologic evaluation of the nipple sections from patient 1 show invasive Paget disease with associated ulceration, with a depth of invasion of 4.5 mm. The breast biomarkers on the nipple section show tumor cells are negative for ER (0%) and PR (0%), and positive for HER2/neu (3+). Additionally, there was a separate 1.5 cm invasive ductal carcinoma, combined Nottingham histologic grade 3, pathologic stage of pT1c. The nipple sections from patient 2 show pigmented, invasive Paget disease, with a 1.5 mm depth of invasion. The tumor cells are positive for CK7 (weak), ER and PR, and negative for HER2/neu (1+). HMB45 and MART1 show increased reactivity in melanocytes. She also had a separate 2.5 cm invasive ductal carcinoma, combined Nottingham histologic grade 3, pathologic stage of pT2.

Conclusion
We present two unique cases of breast invasive Paget disease: one with associated ulceration, which brings challenges with tumor staging; and another one with pigmentation, which can be mistaken as melanoma.
Invasive Paget disease must be distinguished from locally advanced breast cancer presenting as satellite skin nodules or skin ulceration, as it can lead to erroneous tumor over-staging as pT4b. It is important to recognize these two variations of invasive Paget disease so as to avoid over-staging or misdiagnosis, respectively, and to be cognizant of the fact that the treatment and prognosis differ.
Assessment of potential biomarkers for early detection and management of Glomerulonephritis patients with diabetic diseases
Authors: Addissouky T A , Khalil A A , El Agroudy A E 
Published: November 2023

Abstract

Introduction/Objective
Glomerulonephritis is a serious kidney disease that can lead to kidney failure if not detected and treated early. Several potential biomarkers have been identified to aid in early detection of this condition. it is important to investigate and validate these novel biomarkers to improve patient outcomes in the management of glomerulonephritis.

Methods/Case Report
The various biomarkers such as Creatinine, urinary exosomes, Cystatin-C, interleukin-6, tumor necrosis factor-alpha (TNF-α), Fasting blood glucose, Albumin, MicroRNAs, and complement activation factors (C3, C4d) were measured and calculated in 98 infected cases with diabetic patients who had acute kidney diseases. The same biomarkers had been implemented for 87 cases with chronic renal disease on dialysis. Also, the same parameters were determined in 82 healthy persons as controls. Alternative markers' levels were determined by using Microscopic, Biochemical, ELISA, and RT-PCR techniques. The biopsy had been applied only to infected patients.
Imaging diagnostic tools have been applied to all cases.

Results (if a Case Study enter NA)
The studied biomarkers have high sensitivity from 81.35% to 94.72% and accuracy from 88.76% to 96.83% as well as their cut off which approved the aim of this study. Thereafter, the studied markers' reports assisted in detecting glomerulonephritis diseases at early stages.

Conclusion
Alternative biomarkers (Cystatin-C, interleukin-6, tumor necrosis factor-alpha (TNF-α), urinary exosomes, MicroRNAs, and complement activation factors (C3, C4d)) are considered as prospective markers to differentiate healthy individuals from chronic kidney disease by their significant results. Hence, if the studied biomarker has been measured regularly for outpatients who complain of renal diseases, that can be assisted in the early detection of kidney diseases, including glomerulonephritis, and then it can be well managed.
Unusual pattern of microsatellite instability in gastric neuroendocrine tumor
Authors: Lack M , Abdo M E , Hamza A 
Published: November 2023

Abstract

Introduction/Objective
Evaluation of microsatellite instability (MSI) is routinely performed in gastrointestinal tract adenocarcinomas including gastric adenocarcinoma. It confers a good prognosis and is predictive of response to immunotherapy. However, the role of MSI in prognosis and treatment of well differentiated neuroendocrine tumors is controversial. Accordingly, MSI status is not extensively evaluated in neuroendocrine tumors. Limited available literature reports the usual paired losses and loss of MSH6 only in gastric well differentiated neuroendocrine tumor is unheard of. The purpose of this case is to report loss of MSH6 only in a patient with gastric well differentiated neuroendocrine tumor, grade 2.

Methods/Case Report
A 64-year-old female presented with abdominal pain and nausea. Endoscopy revealed erythematous nodules in the stomach which were removed by endoscopic mucosal resection. Microscopically, the tumor had vague nested appearance with areas more infiltrative appearance. However, cytologically tumor cells were bland and monotonous. Immunohistochemical stains showed the tumor cells to be positive for synaptophysin, chromogranin, pancytokeratin, and Cam 5.2, and negative for CK 7, CK 20 and CDX2. Ki-67 proliferation index was 3.7%. Therefore, diagnosis of well differentiated neuroendocrine tumor, grade 2 was rendered. Additionally, MSI by immunohistochemistry was ordered which showed intact nuclear expression of MSH2, MLH1 and PMS2 but loss of nuclear expression for MSH6.

Results (if a Case Study enter NA)
NA

Conclusion
This case highlights the fact that MSI in gastric neuroendocrine tumors can manifest as only MSH6 loss. Whether or not, it is of clinical and prognostic utility, is still up for debate.
Anticoagulant-Related Nephropathy in a Patient on Coumadin
Authors: Almukhtar R , Qu H , Alrammahi A 
Published: November 2023

Abstract

Introduction/Objective
Anticoagulant therapy is commonly used to prevent stroke and systemic embolism in patients with atrial fibrillation. However, it carries the risk of bleeding and can lead to serious complications such as anticoagulant-related nephropathy (ARN), a recently described entity characterized by hematuria and acute kidney injury. This report presents a case of a 79-year-old male with a history a patient with a history of atrial fibrillation on coumadin, highlighting the importance of monitoring for anticoagulant-related complications and the need for prompt diagnosis and management to prevent further renal damage.

Methods/Case Report
The kidney biopsy showed evidence of underlying hypertensive and diabetic nephropathy, with nodular and global glomerulosclerosis, moderate to marked interstitial fibrosis, and tubular atrophy along with many red cell casts of variable ages in the tubules indicative of anticoagulant-related nephropathy. Additionally, one glomerulus had a partial cellular crescent associated with a focus of blood clot, likely related to heavy hematuria.
Patient is seronegative for ANCA. The immunofluorescence microscopy is non-contributory due to absence of glomerulus in the sample.
Electron microscopy showed diffuse foot process effacement and microvillous transformation of podocytes, increased mesangial matrix, and thickened glomerular basement membranes, but no immune complex deposits. these ultrastructural features confirm the background diabetic nephropathy.

Results (if a Case Study enter NA)
NA

Conclusion
Anticoagulant-related nephropathy (ARN) is a rare but serious complication of anticoagulation therapy that can result in hematuria and acute kidney injury. Our case highlights the importance of monitoring for anticoagulant-related complications, especially in high-risk patients with multiple comorbidities. Prompt diagnosis and management of ARN is essential to prevent further renal damage. In this case, despite initial improvement with vitamin K therapy, the patient developed severe renal dysfunction requiring dialysis and renal biopsy. This emphasizes the need for increased awareness and early recognition of ARN in patients on anticoagulant therapy.
Drug-induced thrombotic microangiopathy
Authors: Alrammahi A , Almukhtar R , Qu H 
Published: November 2023

Abstract

Introduction/Objective
Drug-induced thrombotic microangiopathy is observed in the patient on the new cancer therapy. It shares similar pathologic changes, as seen in conventional thrombotic microangiopathy, and is characterized by a pentad of hemolytic anemia, thrombocytopenia, renal dysfunction, fever, and neurological dysfunction. However, some patients may not have full scope of the pentad. Instead, only “diad” (hemolytic anemia and thrombopenia) exists, which could be mistakenly attributed to the drug side effect of bone marrow suppression.

Methods/Case Report
A 71-year-old white male with a history of multiple myeloma (MM) and cardiomyopathy presented with nausea and vomiting following the second round of carfilzomib and pomalidomide chemotherapy.
Laboratory tests showed anemia, thrombocytopenia, and peripheral blood abnormalities such as normocytic erythrocytes with occasional schistocytes, slight left shift in leukocytes, and decreased platelet count.

Results (if a Case Study enter NA)
The biopsy shows diffuse closure of glomerular capillaries, occasional microthrombi and fragmented red cells in glomerular capillaries. Under electron microscope, there are subendothelial space widening, mesangial interposition and wrinkling of glomerular basement membranes. These changes are consistent with acute or subacute thrombotic microangiopathy (TMA).

Conclusion
With the frequent use of advanced chemotherapy drugs, awareness of the drug-induced TMA should be emphasized. Early recognition is important to avoid development of more permanent kidney damage.
INTRAOPERATIVE FROZEN SECTION ANALYSIS OF ENDOMETRIOID OVARIAN BORDERLINE TUMOR: A DIFFICULT DIAGNOSIS
Authors: Jain D , Zaiem F , Ballouk C , Bandyopadhyay S 
Published: November 2023

Abstract

Introduction/Objective
Borderline ovarian tumors (BOT) comprise approximately 15% of all primary ovarian neoplasms; of these endometroid borderline ovarian tumors (EBOT) are much rarer (2-3%). BOT is often potentially misdiagnosed as a malignant tumor based on its challenging histomorphological features and thus, treated aggressively. Herein, we present an unusual case of EBOT with adenofibromatous pattern in a 50-year-old gravida 3, para 2 female diagnosed on intraoperative frozen sections (IOFS).

Methods/Case Report
Patient with history of endometriosis presented with left lower quadrant abdominal pain. MRI revealed complex bilateral ovarian masses with solid and cystic components measuring 5 cm and 6.7 cm in right and left ovary, respectively. An ovarian malignancy was suspected. Patient underwent exploratory laparotomy, total abdominal hysterectomy with bilateral salpingo-opherectomy, and omentectomy. Grossly, bilateral ovaries (BO) showed intact capsule with solid and cystic components. On IOFS, the solid areas demonstrated endometrioid glands arranged in a lobular fashion with squamous morules. The cystic component demonstrated papillary projections with squamous differentiation. Cytology is mildly atypical at best. Based on these findings, a diagnosis of EBOT was made, necessitating staging. Differential diagnoses include atypical endometriosis, endometrioid adenofibroma (EAF) and endometrioid adenocarcinoma (EA). Lack of endometrial stroma surrounding the glands ruled out endometriosis.
Presence of CC with papillary architecture ruled out EAF and lack of destructive stromal invasion with desmoplasia, confluence of glands and significant cytologic atypia ruled out EA. Final histopathological diagnosis of formalin-fixed paraffin-embedded specimen revealed EBOT, pT1bN0M0. Uterus and cervix revealed endometrial hyperplasia with atypia, adenomyosis, leiomyomas, and endocervical polyp.

Results (if a Case Study enter NA)
NA

Conclusion
The accurate diagnosis of BOT during IOFS is critical as it directs surgeons towards staging studies and in choosing conservative surgical treatment over aggressive treatment especially in cases of young women who desire future childbearing. As this is a rare entity, it serves the pathologist well to keep all relevant differential diagnoses in mind.
A rare case of poorly-differentiated endometrial carcinoma in a female-to-male transgender man on testosterone therapy
Authors: Riahi I R , Kang Y , Douglas C , Salani R , Salehiazar S 
Published: November 2023

Abstract

Introduction/Objective
Testosterone is commonly used as gender-affirming therapy for transmasculine individuals. The effects of testosterone therapy on endometrial tissue are complex, with some experiencing atrophy, and others with abnormal uterine bleeding (AUB). Endometrial carcinomas in transgender men are rarely reported in the literature. Here we present a case of poorly-differentiated endometrial carcinoma in a transgender man on testosterone.

Methods/Case Report
A 56 year-old female-to-male transgender man who had been on testosterone and finasteride therapy since 2015 developed vaginal discharge in 2022. No history of abnormal pap smears was noted. The patient’s pelvic ultrasound that was subsequently obtained after presenting with the vaginal discharge showed a thickened endometrium of 4 cm thickness. PET-CT revealed hypermetabolic activity corresponding to the endometrial lining of the uterus. Endometrial biopsy was notable for poorly differentiated carcinoma with retained expression of the mismatch repair proteins by immunohistochemical stains.
The patient underwent hysterectomy with bilateral salpingo-oophorectomy. Grossly, there was a 9.5 cm necrotic mass occupying the entire endometrial cavity, extending &gt;50% into myometrium thickness and extending into the lower uterine segment, without cervical involvement. Background endometrium was inactive/atrophic. Microscopic examination of the tumor showed sheets of epithelioid tumor cells with extensive necrosis, without any glandular pattern. On immunohistochemical stains, the tumor cells were positive for pankeratin and patchy staining for keratin 7 and keratin 20, without expression of PAX8, estrogen receptor, progesterone receptor or androgen receptor.

Results (if a Case Study enter NA)
N/A

Conclusion
Gender-affirming testosterone is a common long-term treatment for transgender men. There is limited understanding of the long-term effects of testosterone therapy on endometrial pathology, particularly regarding the potential for developing malignancy. Positive staining for androgen receptor has been previously reported in endometrial malignancies, and therefore, studies on the potential effects of testosterone therapy on endometrial malignancies is warranted. This case demonstrates the importance of continued gynecologic care in female-to-male transgender individuals who have not undergone previous gender affirming gynecologic surgery.