bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Analysis of 13 Iranian Families With Leukocyte Adhesion Deficiency Type 1
Authors: Teimourian Shahram , De Boer Martin , Roos Dirk , Isaian Anna , Bemanian Mohammad Hassan , Lashkary Sharhzad , Nabavi Mohammad , Arshi Saba , Nateghian Alireza , Sayyahfar Shirin , Sazgara Faezeh , Taheripak Gholamreza , Alipour fayez Elham
Published: May 2018

Background and Aim:

Leukocyte adhesion deficiency type 1 is a rare, autosomal recessive disorder that results from mutations in the ITGB2 gene. This gene encodes the CD18 subunit of β2 integrin leukocyte adhesion cell molecules. Leukocyte adhesion deficiency type 1 is characterized by recurrent bacterial infections, impaired wound healing, inadequate pus formation, and delayed separation of the umbilical cord.

Materials and Methods:

Blood samples were taken from 13 patients after written consent had been obtained. Genomic DNA was extracted, and ITGB2 exons and exon-intron boundaries were amplified by polymerase chain reaction. The products were examined by Sanger sequencing.

Results:

In this study, 8 different previously reported mutations (intron7+1G>A, c.715G>A, c.1777 C>T, c.843del C, c.1768T>C, c.1821C>A, Intron7+1G>A, c.1885G>A) and 2 novel mutations (c.1821C>A; p.Tyr607Ter and c.1822C>T; p.Gln608Ter) were found.

Conclusions:

c.1821C>A (p.Tyr607Ter) and c.1822C>T (p.Gln608Ter) mutations should be included in the panel of carrier detection and prenatal diagnosis.
Haploidentical Donor Transplantation Using a Novel Clofarabine-containing Conditioning Regimen for Very High-risk Hematologic Malignant Neoplasms
Authors: Sharma Akshay , Kang Guolian , Sunkara Anusha , Inaba Hiroto , Jeha Sima , Cross Shane J. , Geiger Terrence , Triplett Brandon
Published: May 2018

Recurrent/refractory hematologic malignancies have a poor prognosis, and there is a need for novel treatment regimens that can be tolerated by this heavily pretreated patient group. Clofarabine has antileukemic activity with an acceptable toxicity profile. In a phase I clinical trial (NCT00824135), we substituted clofarabine for fludarabine in a well-established reduced-intensity conditioning regimen for a T cell–depleted, mismatched-related (haploidentical) donor transplant backbone and explored the maximum tolerated dose of clofarabine in this combination in 15 patients undergoing hematopoietic cell transplantation for recurrent/refractory or secondary leukemia. Clofarabine was well tolerated at a dose of 50 mg/m2/d for 5 days in this regimen, with minimal treatment-related mortality in a heavily pretreated group of high-risk patients. All patients exhibited quick hematopoietic recovery, with median times to neutrophil and platelet engraftment being 11 and 16 days, respectively. Transient elevation of transaminases was the most common toxicity—observed in 13 patients (86.7%), with 6 (40%) grade III or above. Three patients (20%) developed hepatic veno-occlusive disease. Eleven patients (73.3%) died, with the most common cause of death being disease relapse (in 9 patients [60%]), followed by treatment-related mortality (in 2 patients [13.3%]). Four (26.6%) of the patients are long-term survivors.
The Effect of Uncertainty Management Program on Quality of Life Among Vietnamese Women at 3 Weeks Postmastectomy
Authors: Ha Xuan Thi Nhu , Thanasilp Sureeporn , Thato Ratsiri
Published: May 2018

Background

In Vietnam, breast cancer is a top contributor to cancer-related deaths in women. Evidence shows that, after mastectomy, women in Vietnam have a lower quality of life than women in other countries. In addition, high uncertainty is a predictor of low quality of life postmastectomy. Therefore, if nurses can manage uncertainty, the quality of life postmastectomy can improve.

Objective

This study examined the effect of the Uncertainty Management Program (UMP) on quality of life at 3 weeks postmastectomy in Vietnamese women.

Methods

This research was a quasi-experimental study using a “posttest only with control group” design. There were 115 subjects assigned to either the experimental group (n = 57), who participated in the UMP and routine care, or the control group (n = 58), who received only routine care. Participants were assessed 2 times postmastectomy using the modified Quality of Life Index Scale–Vietnamese version.

Results

The experimental group exhibited low uncertainty before discharge and significantly higher quality of life than the control group at 1 and 3 weeks postmastectomy, respectively (P < .05). Women’s physical well-being, psychological well-being, body image concerns, and social concerns were significantly increased with UMP.

Conclusion

The UMP was considered as a promising program that might benefit the QoL of women with breast cancer 3 weeks postmastectomy.

Implications for Practice

The UMP appears feasible to apply for women with breast cancer to improve their QoL postmastectomy in various settings. Nurses can flexibility instruct women in their holistic care attention both in the hospital and at home.
The Association Between Nurse Shift Patterns and Nurse-Nurse and Nurse-Physician Collaboration in Acute Care Hospital Units
Authors: Ma Chenjuan , Stimpfel Amy Witkoski
Published: May 2018

OBJECTIVE

The aim of this study was to examine the impact of nurse shift patterns on nurses' collaboration with nurses and physicians in US acute care hospital units.

BACKGROUND

Collaboration between nurses and other healthcare providers is critical for ensuring quality patient care. Nurses perform collaboration during their shift work; thus, nurse shift patterns may influence collaboration. However, there is a dearth of empirical evidence of the relationship between nurse shift patterns and collaboration of nurses with other healthcare providers.

METHODS

This is a cross-sectional study using data from 957 units in 168 acute care hospitals. Measures of collaboration include nurse-nurse collaboration and nurse-physician collaboration. Measures of shift patterns included shift length and overtime. Multilevel linear regressions were conducted at the unit level, controlling unit and hospital characteristics.

RESULTS

Overtime (more nurses working overtime or longer overtime hours) was associated with lower collaboration at the unit level; however, shift length was not.

CONCLUSIONS

Working overtime may negatively influence nurses' collaboration with other healthcare providers.
Concordance Between FISH Analysis of Her-2/Neu Gene in Breast Duct Carcinoma and Corresponding Axillary Nodal Metastases: Egyptian National Cancer Institute Experience
Authors: Badawy Omnia M. , Hassan Hannan , ELBakey Heba A. , Mosaad Maha
Published: May 2018

Background:

Breast cancer is a major health problem in Egypt. Her-2/Neu gene is routinely assessed for all breast cancer patients primarily by immunohistochemistry. At National Cancer Institute (NCI), Cairo University, Flourescence In Situ hybridization (FISH) analysis of Her-2/Neu gene is carried out for Her-2/Neu score 2 and for some cases of score 3 (particularly those assessed outside NCI). The test is performed essentially on the primary tumor. However, some situations require testing on corresponding lymph node metastases. There is a debate about the concordance between Her-2/Neu status in the primary tumor and synchronous lymph node metastases in various studies.

Aim of the Study:

The aim of this study was to test for the concordance between Her-2/Neu status in the primary breast tumor and corresponding axillary nodal metastases.

Materials and Methods:

This is a retrospective study in which FISH analysis of Her-2/Neu was carried out simultaneously on archived material of 50 cases previously diagnosed as invasive duct carcinoma and the corresponding nodal metastases from the Pathology Department, NCI.

Results:

There was complete concordance between Her-2 status in the primary tumor and the corresponding axillary lymph node metastatic deposits in which Her-2 was amplified in 44% of the studied cohort of Egyptian patients.

Conclusions:

Her-2/Neu gene assessed by FISH analysis on synchronous lymph node metastases is strongly correlated with the primary tumor. Hence, it is justified to carry out the Her-2/Neu test on synchronous lymph nodes to decide on whether to carry out anti-Her-2/Neu target therapy. Further studies on other metastatic sites is recommended.
Evaluation of a Focused Cardiac Ultrasound Protocol in a Pediatric Emergency Department
Authors: Riera Antonio , Weeks Bevin , Emerson Beth L. , Chen Lei
Published: May 2018

Objectives

The objective of this study was to evaluate the implementation of a focused cardiac ultrasound (FoCUS) protocol in a pediatric emergency department (PED).

Methods

We conducted a cross-sectional, observational, quality improvement project in a PED of an urban tertiary care children's hospital. A FoCUS protocol was collaboratively developed by pediatric cardiology and pediatric emergency medicine. This included a reference document with definitions, indications, image acquisition guidelines, and interpretation expectations. We measured physician-sonographer performance against pediatric cardiologist interpretation of stored cine clips as our reference standard. Focused cardiac ultrasound interpretation was dichotomized for the presence or absence of pericardial effusion, depressed left ventricular function, and chamber size abnormalities. Run charts were used to compare the number FoCUS performed each month and the quality of captured cine clips with those from the previous year.

Results

Ninety-two FoCUSs were performed by 34 different physician-sonographers from January to December 2016. The prevalence of FoCUS abnormalities was 18.5%. For pericardial effusion, sensitivity was 100% (95% confidence interval [CI], 48%–100%) and specificity was 99% (95% CI, 94%–100%). For depressed function, sensitivity was 100% (95% CI, 54%–100%) and specificity was 99% (95% CI, 94%–100%). For chamber size abnormalities, sensitivity was 100% (95% CI, 54%–100%) and specificity was 95% (95% CI, 89%–99%). The median number of monthly FoCUS increased from 1 (preprotocol) to 5 (postprotocol), and the median rate of adequate studies increased from 0% to 55%.

Conclusions

We report the collaborative development and successful implementation of a PED FoCUS protocol. Physician-sonographer interpretation of FoCUS yielded acceptable results. Improvements in FoCUS utilization and cine clip adequacy were observed.
Postpartum Depression Screening and Referral in a Pediatric Emergency Department
Authors: Jarvis Lenore R. , Breslin Kristen A. , Badolato Gia M. , Chamberlain James M. , Goyal Monika K.
Published: May 2018

Objectives

The aim of this study was to determine the (1) proportion of screened postpartum depression (PPD)–positive mothers, (2) associated risk factors, and (3) impact of PPD screening in a pediatric emergency department (PED).

Study Design

We performed a pilot cohort study using a convenience sample of mothers (n = 209, all ages) of infant patients 6 months or younger presenting to a PED. Mothers completed a computerized survey that included the Edinburgh Postnatal Depression Scale. We assessed frequency of positive screens and performed multivariable logistic regression to identify associated risk factors. We assessed maternal attitudes toward screening at enrollment and 1-month follow-up with positive-screen mothers. Differences in ED utilization were measured.

Results

Fifty-seven of 209 mothers (27%; 95% confidence interval [CI], 21%–33%) screened positive for PPD, with 14 (7%) reporting suicidal thoughts. Forty-seven percent (97/209) had never previously been screened, including 58% (33/57) of PPD screen–positive mothers. Current unemployment status (adjusted odds ratio [aOR], 2.76; 95% CI, 1.25–6.13) and first-time motherhood (aOR, 3.92; 95% CI, 1.72–8.91) were associated with a positive screen. At 1-month follow-up, mothers (35/37) reported PED-based PPD screening was important. After adjustment for sociodemographic factors, PPD screen–positive mothers had increased PED utilization (aOR, 1.29; 95% CI, 1.03–1.61).

Conclusions

Approximately 1 in 4 mothers screened positive for PPD in a PED, with almost 1 in 10 reporting suicidal thoughts. The majority of PPD screen–positive mothers had not been screened previously. Our study helps to inform future efforts for interventions to support mothers of young infants who use the PED for care.
Lower Extremity Fractures in Hospitalized Pediatric Patients Following Road Traffic Accidents
Authors: Tenenbaum Shay , Bariteau Jason T. , Chechik Ofir , Givon Adi , Peleg Kobi , Thein Ran
Published: May 2018

Lower extremity fractures (LEFs) caused by road traffic accidents (RTAs) can result in significant morbidity and account for a substantial part of nonfatal injuries requiring hospitalization. This study investigated the epidemiology of RTA-associated LEFs in the pediatric population. Based on the National Trauma Registry, data of 28,924 RTA hospitalized pediatric patients were reviewed. Data were analyzed according to LEF mechanism of injury, age distribution, fracture types, associated injuries, surgical treatment, and their interrelations.

A total of 4970 (17.18%) sustained LEFs, with the highest risk for motorcycle-associated RTA, followed by pedestrians. Approximately 1 of 4 patients had multiple fractures. Forty percent (2184 cases) sustained additional injuries, for which car-associated RTAs were at the greatest risk (61%, P < 0.0001), followed by pedestrians and motorcycles (46%–45%, P < 0.0001). Overall, head/neck/face injuries were the most commonly associated injuries. The tibia was the most fractured bone (42%), followed by the femur, fibula, foot, and ankle. This distribution varied according to RTA mechanism. Forty-one percent of cases required fracture treatment in an operating room. As patients were older, the greater the chance they required further treatment in the operating room (P < 0.0001).

This large-scale study on the epidemiology of LEFs in the pediatric population following RTA provides unique information on epidemiological characteristics of LEF, pertinent both to medical care providers and to health policy makers allocating resources and formulating prevention strategies in the attempt to deal with the burden of road traffic accidents.

Level of Evidence: Prognostic and epidemiologic study, level II.
Endometrioid Adenocarcinoma With Solitary Metastasis to the Appendix, Mimicking Primary Appendiceal Adenocarcinoma: A Case Report and Literature Review
Authors: Ma Qiujie , Wu Jianshe
Published: May 2018

Metastatic tumors of the appendix are rare. Endometrial cancer tends to metastasize by directly invading neighboring structures; the lung, liver, bones, and brain are common sites of distant metastasis. Herein, we present a case of a solitary endometrial metastatic tumor in the appendiceal mucosa without serosal involvement that mimicked a primary adenocarcinoma of the appendix. The patient who had undergone a radical hysterectomy for an endometrioid adenocarcinoma 3 years earlier presented to the hospital with a history of persistent right-lower abdominal pain. Physical examination showed tension of the abdominal muscles, tenderness, and rebounding pain on the McBurney’s point. Open appendectomy for suspected appendicitis revealed a perforation of the distal appendiceal tip. Opening of the surgical specimen showed a mass that was located in the mucosa of the appendix near the appendicular root and resembled a primary tumor of the appendix. Microscopically, the adenocarcinoma of the appendiceal mucosa showed a transitional relationship with the normal mucosa, involving the submucosa and muscle but not invading the serosa. Based on the patient’s medical history and the results of immunohistochemical staining, we made a diagnosis of metastatic endometrioid adenocarcinoma. The gross anatomy and histologic features of solitary metastatic tumors can mimic those of primary tumors. A correct diagnosis should be made by combining the patient’s medical history with morphologic and immunohistochemical test results.
Assessment of a Chemotherapy Response Score (CRS) System for Tubo-Ovarian High-Grade Serous Carcinoma (HGSC)
Authors: Ditzel Helena M. , Strickland Kyle C. , Meserve Emily E. , Stover Elizabeth , Konstantinopoulos Panagiotis A. , Matulonis Ursula A. , Muto Michael G. , Liu Joyce F. , Feltmate Colleen , Horowitz Neil , Berkowitz Ross S. , Gupta Mamta , Hecht Jonathan L. , Lin Douglas I. , Jochumsen Kirsten M. , Welch William R. , Hirsch Michelle S. , Quade Bradley J. , Lee Kenneth R. , Crum Christopher P. , Mutter George L. , Nucci Marisa R. , Howitt Brooke E.
Published: May 2018

A chemotherapy response score (CRS) system was recently described to assess the histopathologic response and prognosis of patients with tubo-ovarian high-grade serous carcinoma (HGSC) receiving neoadjuvant chemotherapy. The current study was performed as an independent assessment of this CRS system. We retrospectively identified advanced stage HGSC patients who received neoadjuvant chemotherapy and underwent interval debulking. If available, a hemotoxylin and eosin slide from the omentum and the adnexa was selected for the study. Slides were independently scored by 13 pathologists using the 3-tiered CRS system. Reviewers then received web-based training and rescored the slides. Overall survival and progression-free survival were estimated using the Kaplan-Meier method and compared using the log-rank test. A total of 68 patients with omental (n=65) and/or adnexal (n=59) slides were included in the study. Interobserver reproducibility was moderate for omentum (κ, 0.48) and poor for adnexa (κ, 0.40), which improved for omentum (κ, 0.62) but not for adnexa (κ, 0.38) after online training. For omental slides, a consensus CRS of 1/2 was associated with a shorter median progression-free survival (10.9 mo; 95% confidence interval, 9–14) than a CRS of 3 (18.9 mo; 95% CI, 18–24; P=0.020). In summary, a 3-tiered CRS system of hemotoxylin and eosin–stained omental deposits can yield prognostic information for HGSC patients receiving neoadjuvant chemotherapy, and web-based training improved reproducibility but did not alter determination of clinical outcomes. The CRS system may allow oncologists to identify potential nonresponders and triage HGSC patients for heightened observation and/or clinical trials.
Secondary Tumors of the Gynecologic Tract: A Clinicopathologic Analysis
Authors: Karpathiou Georgia , Chauleur Celine , Hathroubi Sirine , Peoc’h Michel
Published: May 2018

Although the spread of extragenital tumors to individual female genital tract organs, particularly the ovary, has been much studied, histologic data with regard to secondary tumors involving the whole gynecologic tract are largely lacking. Thus, the aim of the study was to investigate the pathologic and clinical features of these tumors in order to better understand their features. This is a retrospective study of 196 secondary lesions involving the gynecologic tract. The parameters studied were the primary site, its histologic type and grade, the presence of mucous production, the type of secondary involvement, defined as distant metastasis, direct extension or locoregional recurrence, and the time to metastasis. Organs involved were the ovary (50%), the vagina (22%), the myometrium (10.7%), the cervix (10.2%), the endometrium (3.6%), the vulva (2%), and the Fallopian tube (1.5%). Most often, primary tumors were colorectal (39.8%), endometrial (15.3%), breast (12.7%), ovarian (10.7%), and gastric (5.6%). Secondary tumors were metachronous in 43.9% of the cases with a mean time to recurrence of 55.5 mo. Distant metastases were the most common type of secondary involvement (64.8%), followed by direct extension (19.9%) and local recurrence (15.3%). Gastrointestinal tumors involved mostly the ovaries, endometrial tumors the vagina, ovarian tumors the myometrium, and urothelial tumors the cervix/vagina (P<0.0001). Vaginal lesions endometrial origin presented with only superficial invasion (P=0.0002). The primary tumor’s features dictate a different pattern of secondary involvement of the gynecologic tract. Endometrial tumors produce mostly superficial vaginal recurrences, mucus-producing gastrointestinal tumors present with ovarian metastases, whereas breast tumors affect the entire gynecologic tract and present the tumors with the most late recurrences.
Morphologic Features of Gastric-type Cervical Adenocarcinoma in Small Surgical and Cytology Specimens
Authors: Turashvili Gulisa , Morency Elizabeth G. , Kracun Mihaela , DeLair Deborah F. , Chiang Sarah , Soslow Robert A. , Park Kay J. , Murali Rajmohan
Published: May 2018

Gastric-type cervical adenocarcinoma (GCA) is a human papillomavirus-unassociated, aggressive, chemorefractory tumor. Well-differentiated examples may exhibit bland morphologic appearances, which could potentially lead to misdiagnosis, particularly in limited material. We sought to characterize the morphologic features of GCA in surgical biopsy and cytology specimens. We identified patients with histologic diagnoses of GCA or minimal-deviation adenocarcinoma between 2004 and 2017. Available slides from biopsy, curettage, and cytology specimens were reviewed. Fifty-nine specimens (37 histology, 22 cytology) were reviewed from 23 patients, including histology specimens alone from 6 patients, cytology specimens alone from 4 patients, and both types of specimen from 13 patients. The median patient age was 52 yr (range, 29–83 yr). Biopsies showed well-to-moderately differentiated adenocarcinomas composed of cells with pale or foamy cytoplasm and well-defined cytoplasmic borders. Nuclei exhibited mild-to-moderate pleomorphism with small nucleoli. The diagnosis was challenging in a minority of biopsies in which neoplastic glandular epithelium was scant, fragmented, and/or well differentiated. Cytology slides showed single and crowded clusters of tumor cells with pale, foamy, and/or vacuolated cytoplasm and well-defined cytoplasmic borders. Nuclei were moderately pleomorphic, round to oval with one or more nucleoli. Of 20 submitted biopsies, GCA was suspected by the submitting pathologist in only 5 (25%) cases. Awareness of the morphologic features and use of confirmatory ancillary studies (eg, immunohistochemistry for markers of gastric differentiation and human papillomavirus testing) will allow accurate diagnosis of these aggressive tumors in biopsy and cytology specimens.
Thickened Endometrium in Postmenopausal Women With an Initial Biopsy of Limited, Benign, Surface Endometrium: Clinical Outcome and Subsequent Pathologic Diagnosis
Authors: Dermawan Josephine K.T. , Hur Christine , Uberti Maria G. , Flyckt Rebecca , Falcone Tommaso , Brainard Jennifer , Abdul-Karim Fadi W.
Published: May 2018

Endometrial biopsy or curetting is indicated for postmenopausal women with abnormal uterine bleeding and/or thickened endometrium. Often, endometrial biopsy or curetting yields limited benign surface endometrium, which may indicate insufficient sampling. This study addresses the clinical outcome and subsequent pathologic diagnoses in postmenopausal women who received this initial diagnosis. Among a total of 370 endometrial biopsy or curetting between 2012 and 2015, 192 (52%) were diagnosed as limited benign surface endometrial epithelium. The women ranged in age from 55 to 91 yr old. Their clinical presentations mainly included postmenopausal bleeding, pelvic pain, and enlarged uterus. Primarily because the initial report was interpreted as “benign,” 108 (57%) had no subsequent follow-up. Interestingly, women with an increased endometrial thickness were more likely to receive repeat evaluation. Among the 84 women who underwent follow-up endometrial sampling, 6 (7%) had hyperplasia with atypia or malignancy, 21 (25%) had a repeat diagnosis of limited surface sample, 4 (5%) had insufficient materials, and 53 (63%) had other benign findings. Among the subset of women who did receive subsequent follow-up, endometrial atypia or malignancies are more likely found in those with increased body mass index. In conclusion, a slight majority of women with postmenopausal bleeding and/or thickened endometrium had an initial limited surface endometrial sample. Most had no subsequent endometrial sampling. Among those with subsequent follow-up, the majority had benign findings. The study highlights the inconsistencies in adequacy criteria for endometrial sampling and the lack of standardization of subsequent management.
Serum response factor mediates nociceptor inflammatory pain plasticity
Authors: Gomez Ruben , Kohler Dorothy M. , Brackley Allison D. , Henry Michael A. , Jeske Nathaniel A.
Published: May 2018

Introduction:

Chronic metabotropic glutamate receptor activation in nociceptive afferents may upregulate A-Kinase Anchoring Protein 150 (AKAP150) expression and/or function.

Objectives:

To quantify transcriptional changes in AKAP150 expression and/or function after long-term mGluR5 agonist exposure, and identify transcriptional elements responsible.

Methods:

Dorsal root ganglia (DRG) were dissected from Sprague-Dawley rats and cultured for biochemical analysis of AKAP150 expression after prolonged mGluR5 agonist exposure. Serum response factor (SRF) expression was knocked down through siRNA in cultures to demonstrate significance to AKAP150 upregulation. Serum response factor was also knocked down in vivo through intrathecal injections of specifically targeted oligonucleotides to demonstrate significance to hyperalgesic priming behavior in persistent mechanical hypersensitivity.

Results:

Serum response factor and AKAP150 are coexpressed in TRPV1(+) DRG neurons in intact DRG. Prolonged mGluR5 agonist exposure increases SRF-dependent transcription and AKAP150 expression in a manner sensitive to protein kinase C inhibition and SRF knock down. Serum response factor in vivo knock down reduces mechanical hyperalgesic priming.

Conclusion:

Serum response factor transcription plays an important role in transcriptional upregulation of AKAP and hyperalgesic priming behavior, and may contribute to the increased role of AKAP150 in the transition from acute to chronic pain.
Fatal Intracranial Hemorrhage Due to Thrombocytopenia in a Patient With Castration-Resistant Prostate Cancer Showing Extensive Bone Uptake of Injected 223Ra Dichloride
Authors: Nakahara Tadaki , Owaki Yoshiki , Kosaka Takeo , Fukada Junichi , Ichimura Akira , Jinzaki Masahiro
Published: May 2018

A 64-year-old man with castration-resistant prostate cancer received 223Ra injection to treat bone metastases. The patient underwent a 223Ra SPECT scan after the first 223Ra injection in which there was increased uptake all over the spine. Spine-to-background activity ratio in the patient was approximately three times greater than normal spine-to-background activity ratios in 223Ra SPECT obtained from the other patients. Eight days after the fifth injection, the patient exhibited a very poor neurologic examination and died of intracranial hemorrhage due to severe thrombocytopenia (platelet counts, 23,000/mm3). The extensive radiation to the spine may have enhanced myelophthisic process in this case.
Herpes Virus Entry Mediator (HVEM) Expression Promotes Inflammation/ Organ Injury in Response to Experimental Indirect-Acute Lung Injury
Authors: Cheng Tingting , Bai Jianwen , Chung Chun-Shiang , Chen Yaping , Fallon Eleanor A. , Ayala Alfred
Published: May 2018

Therapeutic interventions to treat acute lung injury (ALI) remain largely limited to lung-protective strategies, as a real molecular pathophysiologically driven therapeutic intervention has yet to become available. While we have previously documented the expression of herpes virus entry mediator (HVEM) on leukocytes of septic mice and critically ill patients, its functional role in shock/sepsis-induced ALI has not yet been studied. Inasmuch, a murine model of indirect ALI (iALI) was induced by hemorrhagic shock (HEM) followed by cecal ligation and puncture (CLP), septic challenge and HVEM-siRNA or phosphate buffered saline was administrated by intratracheal instillation 2 h after hemorrhage to determine the role of HVEM in the development of experimental iALI. Indices of lung injury were measured. HVEM expression was significantly elevated in iALI mice. Compared with phosphate buffered saline treated iALI mice, HVEM knock-down by siRNA caused a reduction of cytokine/chemokine levels, myeloperoxidase activity, broncho-alveolar lavage fluid (BALF) cell count and protein concentration. HVEM-siRNA treatment reduced inflammation and attenuated pulmonary architecture destruction as well as provided an early (60 h post HEM-CLP) survival benefit in iALI mice. This ability of anti-HVEM treatment to prevent the development of iALI and provide a transient survival benefit implies that mitigating signaling through HVEM may be a novel target worth further investigation.
The Effects of Pharmacological Hypothermia Induced by Neurotensin Receptor Agonist ABS 201 on Outcomes of CPR
Authors: Li Hao , Hua Tianfeng , Wang Wei , Wu Xiaobo , Miao Changqing , Huang Weiping , Xiao Yan , Yang Jin , Bradley Jennifer L. , Peberdy Mary Ann , Ornato Joseph , Dix Thomas A. , Beck Tyler , Tang Wanchun
Published: May 2018

Neurotensin is an endogenous tridecapeptide that binds to neurotensin receptors in the brain, which induce hypothermia. The aim of this study was to investigate whether the receptor agonist ABS 201 could induce therapeutic hypothermia and improve postresuscitation outcomes in a ventricular fibrillation cardiac arrest (VFCA) rat model. VF was electrically induced in 12 rats. Defibrillation was achieved after 6 min of cardiopulmonary resuscitation. After successful resuscitation, animals were randomized to receive ABS 201 (8 mg/kg/h) or placebo. Postresuscitation myocardial function and neurological deficit scores (NDS) were assessed, and postresuscitation survival duration was observed for up to 72 h. After administration of ABS 201, blood temperature decreased significantly from 37°C to 34°C, and was maintained for 2.5 h. There was a significant improvement of postresuscitation myocardial dysfunction, NDS, and survival duration in animals treated with ABS 201. These results demonstrated that ABS 201 induces therapeutic hypothermia in a VFCA rat model, ameliorates postresuscitation myocardial–neurological dysfunction, and prolongs survival duration. ABS 201 may therefore be an alternative method to induce therapeutic hypothermia with current cooling methods and improve postresuscitation outcomes.
Bowel Obstruction and Ventral Hernia After Laparoscopic Versus Open Surgery for Rectal Cancer in A Randomized Trial (COLOR II)
Authors: Petersson Josefin , Koedam Thomas W. , Bonjer H. Jaap , Andersson John , Angenete Eva , Bock David , Cuesta Miguel A. , Deijen Charlotte L. , Fürst Alois , Lacy Antonio M. , Rosenberg Jacob , Haglind Eva
Published: May 2018

Objective:

The aim of this study was to evaluate the risk of bowel obstruction, incisional, and parastomal hernia following laparoscopic versus open surgery for rectal cancer.

Summary Background Data:

Laparoscopic surgery for rectal cancer has been adopted worldwide, after trials reported similar oncological outcomes compared with open surgery. Little is known about long-term morbidity, including bowel obstruction, incisional, and parastomal hernia following surgery.

Methods:

Patients included in the international, multicenter, noninferior, open-label, randomized COLOR II trial were followed for five years. Primary endpoint was local recurrence at 3-year follow-up. Secondary endpoints included bowel obstruction, incisional and parastomal hernia within 5 years, and the current article reports on these secondary endpoints.

Results:

All 1044 patients included in the COLOR II trial were analyzed. There was no difference in risk of bowel obstruction, incisional, or parastomal hernia following laparoscopic or open surgery for rectal cancer.

Conclusion:

Based on long-term morbidity outcomes, laparoscopic surgery for rectal cancer could be considered a routine technique as there are no differences with open surgery.
Resection of the Primary Gastrointestinal Neuroendocrine Tumor Improves Survival With or Without Liver Treatment
Authors: Lewis Aaron , Raoof Mustafa , Ituarte Philip H. G. , Williams John , Melstrom Laleh , Li Daneng , Lee Byrne , Singh Gagandeep
Published: May 2018

Objective:

The aim of this study was to determine outcomes of primary tumor resection in metastatic neuroendocrine tumors across all primary tumor sites.

Background:

Primary tumor resection (PTR) may offer a survival benefit in metastatic gastrointestinal neuroendocrine tumors (GI-NETs); however, few studies have examined the effect of primary site and grade on resection and survival.

Methods:

This is a retrospective study of patients with metastatic GI-NETs at presentation between 2005 and 2011 using the California Cancer Registry (CCR) dataset merged with California Office of Statewide Health Planning and Development (OSHPD) inpatient longitudinal database. Primary outcome was overall survival (OS). Univariate and multivariate (MV) analyses were performed using the Pearson Chi-squared tests and Cox proportional hazard, respectively. OS was estimated using the Kaplan-Meier method and log-rank test.

Results:

A total of 854 patients with GI-NET metastases on presentation underwent 392 PTRs. Liver metastases occurred in 430 patients; 240 received liver treatment(s). PTR improved OS in patients with untreated metastases (median survival 10 vs 38 months, P < 0.001). On MV analysis adjusted for demographics, tumor stage, grade, chemotherapy use, Charlson comorbidity index, primary tumor location, or treatment of liver metastases, PTR with/without liver treatment improved OS in comparison to no treatment [hazard ratio (HR) 0.50, P < 0.001 and 0.39, P < 0.001, respectively]. PTR offered a survival benefit across all grades (low-grade, HR 0.38, P = 0.002 and high-grade, HR 0.62, P = 0.025)

Conclusion:

PTR in GI-NET is associated with a better survival, with or without liver treatment, irrespective of grade. This study supports the resection of the primary tumor in patients with metastatic GI-NETs, independent of liver treatment.
Progressive supranuclear palsy and multiple system atrophy: clinicopathological concepts and therapeutic challenges
Authors: Respondek Gesine , Levin Johannes , Höglinger Günter U.
Published: May 2018

Purpose of review

This update discusses novel aspects on clinicopathological concepts and therapeutic challenges in progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), arising from publications of the last 1.5 years.

Recent findings

The clinical criteria for diagnosis of PSP have been revised. Clinical variability of pathologically defined PSP and MSA makes the development of mature biomarkers for early diagnosis and biomarker-based trial design indispensable. Novel molecular techniques for biomarker supported diagnosis of PSP and MSA and for monitoring disease progression are being studied. Research in the pathophysiology of both diseases generates gradual progress in the understanding of the underlying processes. Several promising disease-modifying therapeutic approaches for PSP and MSA are now moving into clinical trials.

Recent research generates insights in the pathophysiological relevant processes and raises hope for earlier clinical diagnosis and disease-modifying therapies of patients with PSP and MSA.
Comparing the Effects of Atorvastatin With Sodium Valproate (Divalproex) on Frequency and Intensity of Frequent Migraine Headaches: A Double-blind Randomized Controlled Study
Authors: Hesami Omid , Sistanizad Mohammad , Asadollahzade Elnaz , Johari Mohammad-Sadegh , Beladi-Moghadam Nahid , Mazhabdar-Ghashghai Homa
Published: May 2018

Objectives

To evaluate the prophylactic effects of atorvastatin on frequency, intensity, and duration of migraine attacks compared with sodium valproate.

Methods

In this randomized, double-blind, single-center controlled trial, patients with 6 to 15 migraine attacks per month, which were candidates of preventive treatment, were recruited. The patients were randomly allocated into 2 groups. The first group (A) received atorvastatin 40 mg daily, and the second group (B) received sodium valproate 500 mg daily. All patients were visited each month and followed up for 3 months. The characteristics of migraine headaches including frequency, intensity, and duration of attacks were recorded, as well as the number of analgesics taken per each attack and probable adverse effects.

Results

From 100 patients enrolled in the study, 18 cases were excluded owing to adverse effects (2 cases) or lost to follow-up (16 cases). From 82 patients who completed the trial, 46 and 36 were in group A (atorvastatin) and group B (sodium valproate), respectively. Mean age of the patients was not significantly different in the 2 arms of the study (33.56 ± 8.51 in group A and 33.25 ± 9.91 years in group B, P = 0.877). Number, duration, and intensity of attacks and number of analgesics taken during attacks decreased significantly in both groups in monthly follow-ups. However, there was no statistically significant difference between 2 arms of the study in terms of attenuation in the characteristics of migraine attacks. On the other hand, patients in group A suffered fewer adverse effects compared with group B.

Conclusions

This study indicates that atorvastatin could be an alternative for sodium valproate in migraine prophylaxis with comparable efficacy and fewer adverse effects. Multicenter studies with larger sample size are recommended.
ICTV Virus Taxonomy Profile: Togaviridae
Authors: Chen Rubing , Mukhopadhyay Suchetana , Merits Andres , Bolling Bethany , Nasar Farooq , Coffey Lark L. , Powers Ann , Weaver Scott C. ,   ICTV Report Consortium
Published: May 2018

The Togaviridae is a family of small, enveloped viruses with single-stranded, positive-sense RNA genomes of 10–12 kb. Within the family, the genus Alphavirus includes a large number of diverse species, while the genus Rubivirus includes the single species Rubella virus. Most alphaviruses are mosquito-borne and are pathogenic in their vertebrate hosts. Many are important human and veterinary pathogens (e.g. chikungunya virus and eastern equine encephalitis virus). Rubella virus is transmitted by respiratory routes among humans. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Togaviridae, which is available at www.ictv.global/report/togaviridae.
CDK19 is a Regulator of Triple-Negative Breast Cancer Growth
Authors: Hsieh Robert W. , Kuo Angera H. , Scheeren Ferenc A. , Zarnegar Mark A. , Sikandar Shaheen S. , Antony Jane , Heitink Luuk S. , Periyakoil Divya , Kalisky Tomer , Sim Sopheak , Qian Dalong , Malhotra Sanjay V. , Somlo George , Dirbas Frederick M. , Jadhav Ajit , Newman Aaron M. , Clarke Michael F.
Published: May 2018

Triple-negative breast cancer (TNBC) is a poor prognosis disease with no clinically approved targeted therapies. Here, using in vitro and in vivo RNA interference (RNAi) screens in TNBC patient-derived xenografts (PDX), we identify cyclin dependent kinase 19 (CDK19) as a potential therapeutic target. Using in vitro and in vivo TNBC PDX models, we validated the inhibitory effect of CDK19 knockdown on tumor initiation, proliferation and metastases. Despite this, CDK19 knockdown did not affect the growth of non-transformed mammary epithelial cells. Using CD10 and EpCAM as novel tumor initiating cell (TIC) markers, we found the EpCAMmed/high/CD10−/low TIC sub-population to be enriched in CDK19 and a putative cellular target of CDK19 inhibition. Comparative gene expression analysis of CDK19 and CDK8 knockdowns revealed that CDK19 regulates a number of cancer-relevant pathways, uniquely through its own action and others in common with CDK8. Furthermore, although it is known that CDK19 can act at enhancers, our CHIP-Seq studies showed that CDK19 can also epigenetically modulate specific H3K27Ac enhancer signals which correlate with gene expression changes. Finally, to assess the potential therapeutic utility of CDK19, we showed that both CDK19 knockdown and chemical inhibition of CDK19 kinase activity impaired the growth of pre-established PDX tumors in vivo. Current strategies inhibiting transcriptional co-factors and targeting TICs have been limited by toxicity to normal cells. Because of CDK19’s limited tissue distribution and the viability of CDK19 knockout mice, CDK19 represents a promising therapeutic target for TNBC.
SequencEnG: an Interactive Knowledge Base of Sequencing Techniques
Authors: Zhang Yi , Manjunath Mohith , Kim Yeonsung , Heintz Joerg , Song Jun S.
Published: May 2018

Next-generation sequencing (NGS) techniques are revolutionizing biomedical research by providing powerful methods for generating genomic and epigenomic profiles. The rapid progress is posing an acute challenge to students and researchers to stay acquainted with the numerous available methods. We have developed an interactive online educational resource called SequencEnG (acronym for Sequencing Techniques Engine for Genomics) to provide a tree-structured knowledge base of 66 different sequencing techniques and step-by-step NGS data analysis pipelines comparing popular tools. SequencEnG is designed to facilitate barrier-free learning of current NGS techniques and provides a user-friendly interface for searching through experimental and analysis methods. SequencEnG is part of the project KnowEnG (Knowledge Engine for Genomics) and is freely available at http://education.knoweng.org/sequenceng/.
Mycobacterium marinum infection drives foam cell differentiation in zebrafish infection
Authors: Johansen Matt D. , Kasparian Joshua A. , Hortle Elinor , Britton Warwick J. , Purdie Auriol C. , Oehlers Stefan H.
Published: May 2018

Host lipid metabolism is an important target for subversion by pathogenic mycobacteria such as Mycobacterium tuberculosis. The appearance of foam cells within the granuloma are well-characterised effects of chronic tuberculosis. The zebrafish-Mycobacterium marinum infection model recapitulates many aspects of human-M. tuberculosis infection and is used as a model to investigate the structural components of the mycobacterial granuloma. Here, we demonstrate that the zebrafish-M. marinum granuloma contains foam cells and that the transdifferentiation of macrophages into foam cells is driven by the mycobacterial ESX1 pathogenicity locus. This report demonstrates conservation of an important aspect of mycobacterial infection across species.
Refinement of highly flexible protein structures using simulation-guided spectroscopy
Authors: Hays Jennifer M. , Kieber Marissa K. , Li Jason Z. , Han Ji In , Columbus Linda , Kasson Peter M.
Published: May 2018

Highly flexible proteins present a special challenge for structure determination because they are multi-structured yet not disordered, and the resulting conformational ensembles are essential for understanding function. Determining such ensembles is difficult because many measurements that capture multiple conformational populations provide sparse data. A powerful opportunity exists to leverage molecular simulations for spectroscopic experiment selection. We have developed an information-theoretic approach to guide experiments by identifying which measurements best refine the underlying conformational ensemble. We have tested this approach on three flexible bacterial proteins. For proteins where a clear mechanistic hypothesis drives label selection, our approach systematically identifies labels that would test this hypothesis. Furthermore, when available data do not yield an obvious mechanistically-guided label selection strategy, our approach guides label selection and produces conformational refinement that significantly outperforms standard structure-guided approaches. Our information-theoretic approach to label selection thus offers a particular advantage when refining challenging, underdetermined protein conformational ensembles.
Expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD.
Authors: Goodman Lindsey D. , Prudencio Mercedes , Martinez-Ramirez Luis F. , Lan Matthews , Parisi Michael , Petrucelli Leonard , Bonini Nancy M.
Published: May 2018

Expression of an expanded (G4C2)30+ repeat found in C9orf72 is the most prominent mutation in familial FTD and ALS. An unbiased RNAi-based, large-scale screen in (G4C2)49-expressing Drosophila identified the CDC73/PAF1 complex (PAF1C) as a novel suppressor of (G4C2)49-toxicity. Downregulation of PAF1C, an activator of elongating RNAPII, caused suppression by reducing (G4C2)49-RNA levels. Remarkably, only PAF1C components Paf1 and Leo1 were selective for transcription of a long repeat expansion; transcript levels produced from shorter and longer repeat-containing transgenes were similarly affected by other components and Spt4, a previously identified transcriptional regulator of G4C2-repeats. Congruent with our fly data, PAF1 and LEO1 were upregulated in the frontal cortex of C9+ FTD patients and their expression correlated to expression of repeat-containing C9orf72. Surprisingly, this affect was specific to C9+ FTD versus C9+ ALS. This is the first evidence that PAF1C is playing a role in C9orf72-associated FTD. Further, PAF1C may affect other repeat-associated diseases.
Bayesian Networks established functional differences between breast cancer subtypes
Authors: Trilla-Fuertes Lucía , Zapater-Moros Andrea , Gámez-Pozo Angelo , Arevalillo Jorge M , Prado-Vázquez Guillermo , Díaz-Almirón Mariana , Ferrer-Gómez María , López-Vacas Rocío , Navarro Hilario , Espinosa Enrique , Maín Paloma , Vara Juan Ángel Fresno
Published: May 2018

Breast cancer is a heterogeneous disease. In clinical practice, tumors are classified as hormonal receptor positive, Her2 positive and triple negative tumors. In previous works, our group defined a new hormonal receptor positive subgroup, the TN-like subtype, which has a prognosis and a molecular profile more similar to triple negative tumors. In this study, proteomics and Bayesian networks were used to characterize protein relationships in 106 breast tumor samples. Components obtained by these methods had a clear functional structure. The analysis of these components suggested differences in processes such as metastasis or proliferation between breast cancer subtypes, including our new subtype TN-like. In addition, one of the components, mainly related with metastasis, had prognostic value in this cohort. Functional approaches allow to build hypotheses about regulatory mechanisms and to establish new relationships among proteins in the breast cancer context.

Author Summary

Breast cancer classification in the clinical practice is defined by three biomarkers (estrogen receptor, progesterone receptor and HER2) into hormone receptor positive, HER2+ and triple negative breast cancer (TNBC). Our group recently described a new ER+ subtype with molecular characteristics and prognosis similar to TNBC. In this study we propose a mathematical method, the Bayesian networks, as a useful tool to study protein interactions and differential biological processes in breast cancer subtypes, characterizing differences in relevant processes such as proliferation or metastasis and associated them with patient prognosis.