The BCL-2 family member BID plays a role during embryonic development in addition to its BH3-only protein function by acting in parallel to BAX, BAK and BOK.

The intrinsic apoptosis pathway, regulated by the BCL-2 protein family, is essential for embryonic development. Using mice lacking all known apoptosis effectors, BAX, BAK and BOK, we have previously defined the processes during development that require apoptosis. Rare Bok-/- Bax-/- Bak-/- triple knockout (TKO) mice developed to adulthood and several tissues that were thought to require apoptosis during development appeared normal. This raises the question if all apoptosis had been abolished in the TKO mice or if other BCL-2 family members could act as effectors of apoptosis. Here, we investigated the role of BID, generally considered to link the extrinsic and intrinsic apoptosis pathways, acting as a BH3-only protein initiating apoptosis upstream of BAX and BAK. We found that Bok-/- Bax-/- Bak-/- Bid-/- quadruple knockout (QKO) mice have additional developmental anomalies compared to TKO mice, consistent with a role of BID, not only upstream but also in parallel to BAX, BAK and BOK. Mitochondrial experiments identified a small cytochrome c-releasing activity of full-length BID. Collectively, these findings suggest a new effector role for BID in the intrinsic apoptosis pathway.

Predicting VTE and utility of thromboprophylaxis in metastatic and recurrent cervical cancer.

OBJECTIVE: Patients with cervical cancer who are diagnosed with venous thromboembolism (VTE) have worse outcomes compared to those not affected. There has yet to be a reliable method to predict or prevent VTE in cervical cancer patients. Our objective is to describe the incidence of VTE in patients with recurrent and metastatic (r/mCC) and determine risk factors that may predict VTE in this setting. METHODS: We performed an observational cohort study of 386 patients with r/mCC who received at least one line of systemic chemotherapy. We collected demographic, clinical, histologic data and Khorana scores for all patients. Inclusion and exclusion criteria were applied before analysis. Statistical analysis was performed using Pearson chi-square, Student's t-test, and Wilcoxon rank-sum. RESULTS: 232 patients were included for evaluation. Mean age was 49 years (range 20-83). The majority (167, 72%) of patients had squamous cell histology. 169 (72.8%) patients received treatment for recurrent disease and 63 (27.2%) for metastatic, stage IVB disease. 180 (78%) patients received prior radiation and 134 (58%) received bevacizumab. VTE was diagnosed in 89 (38%) patients. There were no statistically significant differences amongst clinical and pathologic characteristics between patients who developed VTE and those who did not. There was no significant association between BMI, Khorana score, radiation, bevacizumab, or immunotherapy and the development of VTE. CONCLUSION: Approximately 40% of patients with r/mCC experienced a new VTE. There were no independent risk factors that could predict VTE in this population. Due to the overwhelmingly high incidence of VTE, prophylactic anticoagulation could be strongly considered in patients with r/mCC.

Isolated para-aortic nodal recurrence after treatment of early stage cervical carcinoma.

OBJECTIVE: Surgical evaluation of lymph node metastasis is paramount in the treatment of cervical cancer. We sought to explore the outcomes of patients with and without para-aortic lymphadenectomy undergoing curative-intent radical hysterectomy for stage IA-IIA cervical cancer. METHODS: Institutional data were retrospectively reviewed to identify women undergoing curative-intent radical hysterectomy with concurrent lymphadenectomy for stage IA-IIA cervical carcinoma from 2004 to 2021. Any carcinoma histology was allowed. Clinical risk stratification was performed according to GOG 92 and GOG 109 protocols. Disease outcomes, patterns of recurrence, and survival were analyzed with Chi square, t-test, Kaplan-Meier, and Cox proportional hazards multivariable statistics. RESULTS: 300 patients were identified, 265 met inclusion criteria. Median follow up was 56 months. Pelvic lymphadenectomy (PLND) was performed in 71%, with the remainder undergoing combined para-aortic dissection (PPaLND). Baseline patient demographics and presence of clinical risk factors were well balanced between groups. PPaLND was more common in patients undergoing open surgery (OR 10.58, p <.0001), and tumors were larger in this group (2.96 vs 2.12 cm, p = .0002) and more likely non-squamous histology (OR 2.02, p = .017). Recurrence of disease was present in 13% of cases, with no difference between PLND and PPaLND regardless of histology. There were zero cases of isolated PaLN recurrence in either group. Neither progression free nor overall survival was different between groups. Prophylactic extended field radiation (EFRT) was not prescribed. CONCLUSION: Omission of PaLN dissection, in the absence of suspicious nodes, did not decrease survival. There were no isolated PaLN recurrences after PLND alone.

Risk factors for catheter-associated urinary tract infections following radical hysterectomy for cervical cancer.

BACKGROUND: Radical hysterectomy is the mainstay of treatment for early-stage cervical cancer. Urinary tract dysfunction is one of the most common complications after radical hysterectomy, and prolonged catheterization has previously been defined as a significant risk factor for catheter-associated urinary tract infections. OBJECTIVE: This study aimed to determine the rate of catheter-associated urinary tract infections after radical hysterectomy for cervical cancer, and to identify additional risk factors for developing catheter-associated urinary tract infections in this population. STUDY DESIGN: We reviewed patients who underwent radical hysterectomy for cervical cancer from 2004 to 2020 after institutional review board approval. All patients were identified from institutional Gynecologic Oncology surgical and tumor databases. The inclusion criterion was radical hysterectomy for early-stage cervical cancer. Exclusion criteria included inadequate hospital follow-up, insufficient records of catheter use in the electronic medical record, urinary tract injury, and preoperative chemoradiation. Catheter-associated urinary tract infection was defined as an infection diagnosed in a catheterized patient or within 48 hours of catheter removal, with significant bacteriuria (>103 cfu/mL) and symptoms or signs attributable to the urinary tract. Data analysis was performed using comparative analysis and univariate and multivariable logistic regression using Excel, GraphPad Prism, and IBM SPSS Statistics. RESULTS: Of the 160 included patients, 12.5% developed catheter-associated urinary tract infections. In univariate analysis, catheter-associated urinary tract infection was significantly associated with current smoking history (odds ratio, 3.76; 95% confidence interval, 1.39-10.08), minimally invasive surgical approach (odds ratio, 5.24; 95% confidence interval, 1.91-16.87), estimated surgical blood loss >500 mL (odds ratio, 0.18; 95% confidence interval, 0.04-0.57), operative time >300 minutes (odds ratio, 2.92; 95% confidence interval, 1.07-9.36), and increased duration of catheterization (odds ratio, 18.46; 95% confidence interval, 3.67-336). After adjusting for interactions and controlling for potential confounders with multivariable analysis, current smoking history and catheterization for >7 days were identified as independent risk factors for development of catheter-associated urinary tract infections (adjusted odds ratio, 3.94; 95% confidence interval, 1.28-12.37; adjusted odds ratio, 19.49; 95% confidence interval, 2.78-427). CONCLUSION: Preoperative smoking cessation interventions for current smokers should be implemented to decrease risk for postoperative complications, including catheter-associated urinary tract infections. In addition, catheter removal within 7 postoperative days should be encouraged in all women undergoing radical hysterectomy for early-stage cervical cancer in an effort to decrease infection risk.

Mixed measures: different definitions of racially diverse neighborhoods compared.

Focusing on neighborhoods that researchers consider particularly diverse, this paper assesses the ways scholars have characterized neighborhood racial diversity in the United States. Social scientists use a variety of methods to define and measure highly racially diverse places, resulting in a single label being used to capture very different aspects of a census tract's racial demography. We examine the criteria used to classify neighborhood racial diversity to bring perspective on the logic behind various approaches. We then group the range of schemas into several broad types from which we choose a representative four. These form the basis for a series of empirical comparisons using U.S. Census data to reveal the contexts where the taxonomies produce similar outcomes and those where they do not. The analysis goes on to consider the implications stemming from the choices social scientists make when they opt for one approach over another.

Evacuees and Migrants Exhibit Different Migration Systems After the Great East Japan Earthquake and Tsunami.

Research on the destinations of environmentally induced migrants has found simultaneous migration to both nearby and long-distance destinations, most likely caused by the comingling of evacuee and permanent migrant data. Using a unique data set of separate evacuee and migration destinations, we compare and contrast the pre-, peri-, and post-disaster migration systems of permanent migrants and temporary evacuees of the Great East Japan Earthquake and Tsunami. We construct and compare prefecture-to-prefecture migration matrices for Japanese prefectures to investigate the similarity of migration systems. We find evidence supporting the presence of two separate migration systems-one for evacuees, who seem to emphasize short distance migration, and one for more permanent migrants, who emphasize migration to destinations with preexisting ties. Additionally, our results show that permanent migration in the peri- and post-periods is largely identical to the preexisting migration system. Our results demonstrate stability in migration systems concerning migration after a major environmental event.

Remaking White Residential Segregation: Metropolitan Diversity and Neighborhood Change in the United States.

Between 1990 and 2010, the white population share in US metropolitan areas fell from 73.5 percent to 60.3 percent. This paper explores how this decline affected the number and composition of white census tracts (tracts in which non-Latino whites constitute the largest group). In 1990, white tracts comprised 82 percent of all metropolitan tracts. By 2010, this percentage had fallen to 70 percent, paralleling the percentage point drop in white population share. This loss was concentrated among the most segregated white tracts - those with low diversity. White tracts that were moderately diverse actually doubled in number between 1990 and 2010 although this increase was insufficient to cancel the loss of low diversity white tracts. We model the effects of metropolitan characteristics on white-tract change by metropolitan area. Greater metropolitan-scale diversity increases the probability that low-diversity white tracts transition to moderate-diversity white. Moderately diverse white tracts, however, become more stable with increased diversity. A large metropolitan percentage of blacks or the foreign born, however, reverses this stabilizing effect, increasing the probability that moderately diverse white tracts transition to non-white tracts (i.e. where a non-white group is the largest group). Thus the level and composition of metropolitan diversity matters for the trajectory of moderately diverse white tracts. Overall, the formation of new white tracts, possibly the result of gentrification, coupled with the emergence of moderately diverse white tracts and an increasing share of whites living in such residential environments, suggests a reconfiguration rather than a dissolving of white dominated neighborhood space in response to increased diversity in surrounding metropolitan contexts.

Novel dengue virus NS2B/NS3 protease inhibitors.

Dengue fever is a severe, widespread, and neglected disease with more than 2 million diagnosed infections per year. The dengue virus NS2B/NS3 protease (PR) represents a prime target for rational drug design. At the moment, there are no clinical PR inhibitors (PIs) available. We have identified diaryl (thio)ethers as candidates for a novel class of PIs. Here, we report the selective and noncompetitive inhibition of the serotype 2 and 3 dengue virus PR in vitro and in cells by benzothiazole derivatives exhibiting 50% inhibitory concentrations (IC50s) in the low-micromolar range. Inhibition of replication of DENV serotypes 1 to 3 was specific, since all substances influenced neither hepatitis C virus (HCV) nor HIV-1 replication. Molecular docking suggests binding at a specific allosteric binding site. In addition to the in vitro assays, a cell-based PR assay was developed to test these substances in a replication-independent way. The new compounds inhibited the DENV PR with IC50s in the low-micromolar or submicromolar range in cells. Furthermore, these novel PIs inhibit viral replication at submicromolar concentrations.

Three colossal neurons: a new approach to an old classroom demonstration.

Research suggests that the key to optimal student learning, regardless of class size, is engaging students in active learning. It is my contention that to truly understand neural processing, one must not only understand the activities of the neuron as a living cell, but also how that cell works within the context of a neural network. The demonstration exercise described herein combines techniques expressed in three previously published articles, with certain modifications, allowing as few as 15 and as many as about 200 students to actively participate in the endeavor. Moreover, test scores from 158 students were examined, showing that students who participated in the demonstration performed significantly better on exam questions than students who did not take part.

Docetaxel treatment for widely metastatic invasive vulvar extramammary Paget's disease with multifocal bone metastasis.

•Invasive extramammary Paget's disease of the vulva is rare.•Distant metastasis has a very poor prognosis.•Given rarity of disease, no standardized treatment exists.•Single agent docetaxel is a viable treatment for metastatic invasive extramammary Paget's disease.

On Target: An Intrapulmonary Transplantation Method for Modelling Lung Tumor Development in its Native Microenvironment.

The development of in vivo lung cancer models that faithfully mimic the human disease is a crucial research tool for understanding the molecular mechanisms driving tumorigenesis. Subcutaneous transplantation assays are commonly employed, likely due to their amenability to easily monitor tumor growth and the simplistic nature of the technique to deliver tumor cells. Importantly however, subcutaneous tumors grow in a microenvironment that differs from that resident within the lung. To circumvent this limitation, here we describe the development of an intrapulmonary (iPUL) orthotopic transplantation method that enables the delivery of lung cancer cells, with precision, to the left lung lobe of recipient mice. Critically, this allows for the growth of lung cancer cells within their native microenvironment. The coupling of iPUL transplantation with position emission tomography (PET) imaging permits the serial detection of tumors in vivo and serves as a powerful tool to trace lung tumor growth and dissemination over time in mouse disease models.

Housing unit and urbanization estimates for the continental U.S. in consistent tract boundaries, 1940-2019.

Subcounty housing unit counts are important for studying geo-historical patterns of (sub)urbanization, land-use change, and residential loss and gain. The most commonly used subcounty geographical unit for social research in the United States is the census tract. However, the changing geometries and historically incomplete coverage of tracts present significant obstacles for longitudinal analysis that existing datasets do not sufficiently address. Overcoming these barriers, we provide housing unit estimates in consistent 2010 tract boundaries for every census year from 1940 to 2010 plus 2019 for the entire continental US. Moreover, we develop an "urbanization year" indicator that denotes if and when tracts became "urbanized" during this timeframe. We produce these data by blending existing interpolation techniques with a novel procedure we call "maximum reabsorption." Conducting out-of-sample validation, we find that our hybrid approach generally produces more reliable estimates than existing alternatives. The final dataset, Historical Housing Unit and Urbanization Database 2010 (HHUUD10), has myriad potential uses for research involving housing, population, and land-use change, as well as (sub)urbanization.

Tumoral Morphologic Features From Cervical Biopsies That Are Predictive of a Negligible Risk for Nodal Metastasis and Tumor Recurrence in Usual-type Cervical Adenocarcinomas: A Multi-institutional Study.

The metastatic or recurrent potential of localized human papillomavirus-associated endocervical adenocarcinoma (HPVA EAC) is difficult to predict, especially based upon biopsy alone. Recent analyses of small cohorts indicate that high tumor nuclear grade (TNG) and the presence of necrotic tumor debris (NTD) from HPVA EACs in cervical biopsy specimens are highly predictive of nodal metastasis (NM). In the present study, we aimed to investigate how reliably tumoral morphologic features from cervical biopsy specimens predict NM or tumor recurrence (TR) and patient outcomes in a large cohort of endocervical adenocarcinoma patients. A cohort comprised of 397 patients with HPVA EAC treated at 18 institutions was identified, and cervical biopsies were paired with their associated complete tumor resections for a total of 794 specimens. A variety of tumoral histologic features were examined for each paired specimen, including TNG (assessed on a 3-tiered scale of increasing abnormalities-TNG1, TNG2, TNG3) and NTD (defined by the presence of necrotic and apoptotic tumor cells within tumor glandular lumens admixed with granular and eosinophilic amorphous material and inflammatory cells), which were correlated with outcomes. The distribution of TNG in biopsies was as follows: 86 (21.7%) TNG1, 223 (56.2%) TNG2, and 88 (22.2%) TNG3. NTD was identified in 176 (44%) of the biopsy specimens. The sensitivity, specificity, positive predictive value, and negative predictive value of a TNG1 assignment in the biopsy being predictive of the same assignment in the full resection were 0.82 (95% confidence interval [CI]: 0.7-0.9), 0.895 (0.86-0.93), 0.593 (0.48-0.696), and 0.96 (0.94-0.98), respectively. Respective values for an NTD-negative status were 0.89 (95% CI: 0.83-0.92), 0.715 (0.64-0.77), 0.72 (0.65-0.77), and 0.89 (0.83-0.93), respectively. Compared with the other cases in each category, both TNG1 and an NTD-negative status were each significantly associated with lower rates of NM (odds ratio for TNG1=0.245, 95% CI: 0.070-0.857, P=0.0277; for NTD=0.199, 95% CI: 0.094-0.421, P<0.0001) and TR (odds ratio for TNG1=0.225, 95% CI: 0.051-0.987, P=0.0479; for NTD=0.367, 95% CI: 0.171-0.786, P=0.0099) independent of depth of stromal invasion, lymphovascular invasion, tumor size, FIGO stage, and Silva pattern. Overall, 73/379 (19%) cases were both TNG1 and NTD-negative on the biopsy, and none of these 73 cases showed NM (0%), but a single case (1.4%) showed TR. In contrast, among the 324 biopsies with TNG2/3 and/or presence of NTD, 62 (19.1%) had NM, and 41 (12.9%) had TR. In summary, 2 variables in combination (ie, TNG1 and NTD-negative) identified a subset of HPVA EAC patients-∼19%-with a 0% frequency of nodal metastases and only 1.4% frequency of recurrence. Biopsies highly but imperfectly predicted these features. Nonetheless, these findings may potentially be of clinical utility in the risk stratification of patients with HPVA EACs. This may allow some patients with a minimal risk of nodal metastases and TR to be identified at the biopsy phase, thereby facilitating more personalized, possibly less aggressive treatment.

Tumor Necrotic Debris and High Nuclear Grade: Newly Identified High-risk Factors for Early-stage Endocervical Adenocarcinoma.

OBJECTIVE: Invasive pattern of endocervical adenocarcinomas (EACs) is known to influence lymph node metastasis and cancer recurrence. In this study we describe the prognostic significance of necrotic tumor debris (NTD) and tumor nuclear grade on recurrence risk stratification of early-stage cervical adenocarcinoma. METHODS: Patients who underwent surgery from 2007 to 2018 for International Federation of Gynecology and Obstetrics (FIGO) stage IA1-IB2 EAC, for whom pathology was available for review were included in this study. Clinico-pathologic variables and clinical recurrence risk stratification (low, intermediate, or high risk) were correlated to intraluminal NTD and tumor nuclear grade (N3). RESULTS: Among 50 patients meeting inclusion criteria, all were managed surgically and clinically risk stratified as low (n=33), intermediate (n=13), and high risk (n=4). Twenty-three patients (46%) were NTD-N3 negative and 27 (54%) were NTD-N3 positive. NTD-N3 was significantly associated with higher stage, tumor grade, larger tumor size, positive lymphovascular space invasion, and recurrence of disease (P=0.025). Patients with stage IB1 EAC who were stratified as intermediate or high-risk for recurrence were positive for NTD-N3. Lack of NTD-N3 had 100% negative predictive value for disease recurrence. CONCLUSIONS: NTD-N3, a novel pathologic finding, may be used to further stratify overall recurrence risk, and may play a role in individualization of patient care in early-stage EAC.

The Instability of Highly Racially Diverse Residential Neighborhoods in the United States.

This research concerns the location and stability of highly racially diverse census tracts in the United States. Like some other scholars, the authors define such tracts conservatively, requiring the significant presence of at least three racialized groups. Of the approximately 65,000 tracts in the country, there were 197 highly diverse tracts in 1990 and 998 in 2010. Most were located in large metropolitan areas. Stably integrated highly diverse tracts were the exception rather than the rule. The vast majority of highly diverse tracts transitioned to that state from being predominantly White. Those that transitioned from being highly racially diverse were most likely to transition to being majority Latino. Although the absolute level of metropolitan racial diversity has no effect on the stability of high-diversity tracts, change in both metropolitan-scale racial diversity and population raise the probability of a tract's transitioning to high diversity. Metropolitan-scale racial diversity did not affect the stability of highly diverse tracts, but it did alter the patterns of succession from them. The authors also found that highly diverse tracts were unstable and less likely to form in metropolitan areas with high percentages of Blacks. Increased metropolitan-level diversity mutes this Black population share effect by reducing the probability of high-diversity tract succession to a Black majority.

Cervical Adenocarcinoma: Histopathologic Features From Biopsies to Predict Tumor Behavior.

The pattern-based classification system of endocervical adenocarcinoma correlates with nodal metastasis and clinical outcomes, but its application in biopsies is challenging. The aim of this study was the correlation of additional histologic features with patterns of invasion as well as prognosis. A total of 103 specimens from 71 cervical adenocarcinoma cases were studied. Among the 71 cases, all had resection specimens including hysterectomy, cold knife cone excision or loop electrosurgical excision procedure excision, and 32 of these had prior cervical biopsies. We applied the pattern-based classification system to all the specimens and evaluated histopathologic features microscopically. Findings in biopsies were compared with their corresponding resections and correlated with nodal status and disease stage. In 71 resection specimens, pattern A was present in 10 (14.1%), pattern B in 12 (16.9%), and pattern C in 49 (69%) cases. Of the 32 cervical biopsies, pattern of invasion could be classified in only 16 (50%) cases, including 1 (6%) with pattern A, 4 (25%) with pattern B, and 11 (69%) with pattern C. Of the 32 cervical biopsies, 30 could be evaluated for intraluminal necrotic/tumor debris and/or grade 3 nuclei, which correlated with pattern C as well as with lymph node metastasis in the subsequent staging specimens. No tumor with patterns A or B had intraluminal necrotic/tumor debris or grade 3 nuclei in either biopsy or resection specimens. Therefore, intraluminal necrotic/tumor debris and grade 3 nuclei are highly predictive histologic features for cervical adenocarcinomas with pattern C invasion and nodal metastasis.

Predicting neighborhood racial change in large US metropolitan areas, 1990-2010.

Neighborhoods in US metropolitan areas experienced dramatic changes in racial composition during the 1990s and again during the 2000s. We ask to what extent does the recent period of neighborhood racial change reflect an extension of the local processes operative in the 1990s, processes characteristic of large metropolitan areas or the nation more generally, or reflect new dynamics. After classifying neighborhoods in US metropolitan areas into different types based on their racial composition and having harmonized a set of tracts to consistent boundaries, we use metropolitan-scale tract transition matrices from the 1990s to predict changes in neighborhood racial mix between 2000 and 2010. To capture scale effects, we repeat this using a set of pooled metropolitan-scale tract transition matrices and again using a national tract transition matrix. We show that the main dynamic at work across the metropolitan system is the underprediction of moderately diverse white majority tracts: i.e., in the 2000s, the rate of increase in the racial diversity of white majority tracts that transitioned from being predominantly white to moderately diverse was much higher than expected based on 1990s trends. In some metropolitan areas, shares of moderately diverse white tracts in 2010 are anticipated by their 1990s neighborhood dynamics, suggesting temporal stability and a locational specificity in these processes. Others experience a temporal rupture in these dynamics, and their moderately diverse white tract share is better anticipated by pooling transition information. The study also invites us to think about the nature of residential change currently taking place that we can capture in 2020 census data.

Phage display antibodies to allelic determinants of canine blood cells.

Techniques were developed to select useful allele-specific antibodies directed to canine red blood cell alloantigens from a phage display library in which antibody single chain variable fragments (scFv) were expressed on filamentous bacteriophage. First, techniques were developed to detect specific antigens displayed on red blood cells using flow cytometry. Next, techniques permitting the efficient selection of red blood cell binders from a large phage library were developed. Finally, the amplified library was depleted using the red blood cells of one animal and the remainder enriched using cells from a genetically different animal. A high frequency of clones derived from this population bound antigen(s) of the second animal but not the first. Sequence analysis of these clones revealed that at least 11 clonally distinct isolates were present within the selected population. The procedure used to obtain these reagents is simple and inexpensive and the techniques developed should find applications in canine transfusion medicine and parentage assignment.