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When firm implantation has occurred, pregnancy losses during the late embryonic or early fetal period are less common and typically occur before 60 days of gestation. A rare case of early fetal death due to Geotrichum candidum infection in a pluriparous Jersey crossbred cow was sporadically recorded during routine screening at the university cattle farm. The early fetal death was diagnosed using sequential sonographic examinations, and the aetiology was confirmed through microbiological examination and histopathological evaluation of an endometrial biopsy sample. It is concluded that, although mycotic abortions and fetal deaths are uncommon and sporadic, routine screening of cows for late embryonic and early fetal death remains essential. [ABSTRACT FROM AUTHOR]

This article discusses a case report of a patient with sickle cell disease (SCD) who underwent a donor-specific antibody desensitization treatment using daratumumab prior to a hematopoietic cell transplant. The patient had a history of red cell antibodies and high levels of HLA antibodies, which increased the risk of graft failure. Traditional pretransplant immune suppression methods were ineffective, so the patient received daratumumab along with other treatments, resulting in a reduction in antibody levels. The patient successfully underwent the transplant and achieved full donor chimerism with no evidence of graft-versus-host disease. This is the first reported use of daratumumab for this indication in SCD. The document also includes a table summarizing three different studies on patients who underwent allogeneic hematopoietic cell transplantation (AlloHCT), providing information on various factors such as desensitization regimens and donor chimerism. The authors acknowledge funding support and declare any conflicts of interest. [Extracted from the article]

We sought to perform a systematic review and individual participant data meta‐analysis to identify predictors of treatment response following thalamic neuromodulation in pediatric patients with medically refractory epilepsy. Electronic databases (MEDLINE, Ovid, Embase, and Cochrane) were searched, with no language or data restriction, to identify studies reporting seizure outcomes in pediatric populations following deep brain stimulation (DBS) or responsive neurostimulation (RNS) implantation in thalamic nuclei. Studies featuring individual participant data of patients with primary or secondary generalized drug‐resistant epilepsy were included. Response to therapy was defined as >50% reduction in seizure frequency from baseline. Of 417 citations, 21 articles reporting on 88 participants were eligible. Mean age at implantation was 13.07 ± 3.49 years. Fifty (57%) patients underwent DBS, and 38 (43%) RNS. Sixty (68%) patients were implanted in centromedian nucleus and 23 (26%) in anterior thalamic nucleus, and five (6%) had both targets implanted. Seventy‐four (84%) patients were implanted bilaterally. The median time to last follow‐up was 12 months (interquartile range = 6.75–26.25). Sixty‐nine percent of patients achieved response to treatment. Age, target, modality, and laterality had no significant association with response in univariate logistic regression. Until thalamic neuromodulation gains widespread approval for use in pediatric patients, data on efficacy will continue to be limited to small retrospective cohorts and case series. The inherent bias of these studies can be overcome by using individual participant data. Thalamic neuromodulation appears to be a safe and effective treatment for epilepsy. Larger, prolonged prospective, multicenter studies are warranted to further evaluate the efficacy of DBS over RNS in this patient population where resection for curative intent is not a safe option. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to better understand the long‐term palliative and disease‐modifying effects of surgical resection beyond seizure freedom, including frequency reduction and both late recurrence and remission, in patients with drug‐resistant epilepsy. Methods: This retrospective database‐driven cohort study included all patients with >9 years of follow‐up at a single high‐volume epilepsy center. We included patients who underwent lobectomy, multilobar resection, or lesionectomies for drug‐resistant epilepsy; we excluded patients who underwent hemispherectomies. Our main outcomes were (1) reduction in frequency of disabling seizures (at 6 months, each year up to 9 years postoperatively, and at last follow‐up), (2) achievement of seizure remission (>6 months, >1 year, and longest duration), and (3) seizure freedom at last follow‐up. Results: We included 251 patients; 234 (93.2%) achieved 6 months and 232 (92.4%) experienced 1 year of seizure freedom. Of these, the average period of seizure freedom was 10.3 years. A total of 182 (72.5%) patients were seizure‐free at last follow‐up (defined as >1 year without seizures), with a median 11.9 years since remission. For patients not completely seizure‐free, the mean seizure frequency reduction at each time point was 76.2%, and ranged from 66.6% to 85.0%. Patients decreased their number of antiseizure medications on average by.58, and 53 (21.2%) patients were on no antiseizure medication at last follow‐up. Nearly half (47.1%) of those seizure‐free at last follow‐up were not seizure‐free immediately postoperatively. Significance: Patients who continue to have seizures after resection often have considerable reductions in seizure frequency, and many are able to achieve seizure freedom in a delayed manner. [ABSTRACT FROM AUTHOR]

Summary: We adjusted haematopoietic stem and progenitor cell (HSPC) apheresis collection from patients with sickle cell disease (SCD) by targeting deep buffy coat collection using medium or low collection preference (CP), and by increasing anticoagulant–citrate–dextrose–solution A dosage. In 43 HSPC collections from plerixafor‐mobilized adult patients with SCD, we increased the collection efficiency to 35.79% using medium CP and 82.23% using low CP. Deep buffy coat collection increased red blood cell contamination of the HSPC product, the product haematocrit was 4.7% with medium CP and 6.4% with low CP. These adjustments were well‐tolerated and allowed efficient HSPC collection from SCD patients. [ABSTRACT FROM AUTHOR]

Summary: It is not known whether obesity has a differential effect on allogeneic haematopoietic cell transplantation outcomes with alternative donor types. We report the results of a retrospective registry study examining the effect of obesity [body mass index (BMI) > 30] on outcomes with alternative donors (haploidentical related donor with two or more mismatches and receiving post‐transplant cyclophosphamide [haplo] and cord blood (CBU)] versus matched unrelated donor (MUD). Adult patients receiving haematopoietic cell transplantation for haematologic malignancy (2013–2017) (N = 16 182) using MUD (n = 11 801), haplo (n = 2894) and CBU (n = 1487) were included. The primary outcome was non‐relapse mortality (NRM). The analysis demonstrated a significant, non‐linear interaction between pretransplant BMI and the three donor groups for NRM: NRM risk was significantly higher with CBU compared to haplo at BMI 25–30 [hazard ratio (HR) 1.66–1.71, p < 0.05] and MUD transplants at a BMI of 25–45 (HR, 1.61–3.47, p < 0.05). The results demonstrated that NRM and survival outcomes are worse in overweight and obese transplant recipients (BMI ≥ 25) with one alternative donor type over MUD, although obesity does not appear to confer a uniform differential mortality risk with one donor type over the other. BMI may serve as a criterion for selecting a donor among the three (MUD, haplo and CBU) options, if matched sibling donor is not available. [ABSTRACT FROM AUTHOR]

Imparting epithelial to mesenchymal transition (EMT) during cellular transformation, a major driving force behind tumor progression, is one of the notorious oncogenic activities of transforming growth factor β (TGFβ); however, the secretary factors released during TGFβ‐induced EMT that may have role in potentiating EMT and tumor progression are poorly known. This study was undertaken to identify such secreted protein factors from TGFβ‐induced A549 cells cultured in serum‐free chemically defined medium (FreestyleTM) using Matrix Assisted Laser Desorption Ionization‐Time of flight/Time of flight (MALDI‐TOF/TOF) mass spectrometry. We identified some of the potential factors such as ESR, ANXA2, ALDH1A, TGFβ‐induced protein ig‐h3, and PAI‐1 that were not only secreted but some were also elevated in TGFβ‐induced A549 cells. Interestingly, these factors are widely reported to play crucial role in EMT induction and progression, which not only validates our findings but also opens avenues for further investigation, if upon secretion they act exogenously through certain receptors to potentiate cellular signaling involved in EMT induction and tumor progression. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T‐cell (CAR T‐cell) therapy is associated with significant toxicities secondary to immune activation, including a rare but increasingly recognised severe toxicity resembling haemophagocytic lymphohistiocytosis (carHLH). We report the development of carHLH in 14·8% of paediatric patients and young adults treated with CD19‐specific CAR T‐cell therapy with carHLH, occurring most commonly in those with high disease burden. The diagnosis and treatment of carHLH required a high index of suspicion and included multidrug immunomodulation with variable response to therapies. Compared to patients without carHLH, patients with carHLH had both reduced response to CAR T‐cell therapy (P‐value = 0·018) and overall survival (P‐value = < 0·0001). [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancers (TNBC) are highly aggressive and drug resistant accounting for majority of cases with poor outcome. Purified natural compounds display substantial anticancer activity with reduced cytotoxicity providing a new avenue to combat TNBC. Chebulinic acid (CA), a polyphenol derived from the fruits of various medicinal plants has potent anticancer activity. Here, we demonstrate that CA shows significant cytotoxicity against triple negative MDA‐MB‐231 cells. CA exhibited cytotoxicity to MDA‐MB‐231 cells in 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. Further, CA mitigated MDA‐MB‐231 cells viability and proliferation as shown by reduced live cell count, crystal violet staining, colony formation assay, soft agar assay and cell cycle analysis. Wound healing assay and trans‐well migration assay demonstrated that CA significantly inhibited migration of MDA‐MB‐231 cells. Also reduced MMP9 expression was observed in CA‐treated cells by gelatin zymography. CA negatively regulated mesenchymal characteristics of MDA‐MB‐231 cells demonstrated by F‐actin staining and reduced expression of N‐cadherin by confocal microscopy and western blot analysis. Annexin V/propidium iodide (PI) and active caspase‐3 staining showed that CA was able to induce apoptosis in MDA‐MB‐231 cells but did not activate caspase‐3. Two‐dimensional gel electrophoresis based proteomic analysis demonstrated that CA regulated proteins belonging to the oxidative stress pathway, apoptotic pathway and proteins with antiproliferative activity. Western blot analysis analysis revealed that CA negatively regulated superoxide dismutase 1 (SOD1) and enhanced oxidative stress in MDA‐MB‐231 cells. SOD1 in‐gel activity assay also showed reduced SOD1 activity upon CA treatment. Overexpression studies with GFP‐LC3 and tandem tagged RFP‐GFP‐LC‐3 also demonstrated enhanced autophagy upon CA treatment. [ABSTRACT FROM AUTHOR]

Apoptosis is an organised ATP‐dependent programmed cell death that organisms have evolved to maintain homoeostatic cell numbers and eliminate unnecessary or unhealthy cells from the system. Dysregulation of apoptosis can have serious manifestations culminating into various diseases, especially cancer. Accurate control of apoptosis requires regulation of a wide range of growth enhancing as well as anti‐oncogenic factors. Appropriate regulation of magnitude and temporal expression of key proteins is vital to maintain functional apoptotic signalling. Controlled protein turnover is thus critical to the unhindered operation of the apoptotic machinery, disruption of which can have severe consequences, foremost being oncogenic transformation of cells. The ubiquitin proteasome system (UPS) is one such major cellular pathway that maintains homoeostatic protein levels. Recent studies have found interesting links between these two fundamental cellular processes, wherein UPS depending on the cue can either inhibit or promote apoptosis. A diverse range of E3 ligases are involved in regulating the turnover of key proteins of the apoptotic pathway. This review summarises an overview of key E3 ubiquitin ligases involved in the regulation of the fundamental proteins involved in apoptosis, linking UPS to apoptosis and attempts to emphasize the significance of this relationship in context of cancer. [ABSTRACT FROM AUTHOR]

E6AP (E6 associated protein) is a HECT domain containing protein having dual E3 ligase and ERα coactivation activity in breast cancer cells. Although E6AP is known to possess antitumorigenic activity, the underlying molecular mechanism is poorly understood. In the present study, we applied nano‐LC based proteomics approach to identify E6AP‐interacting proteins where we performed GST‐pull down using GST‐E6AP from whole cell extracts of MCF7 cells, resolved the differentially interacting proteins on 1D‐SDS‐PAGE, excised the gel bands that were trypsin digested followed by fractionation and spotting on MALDI‐TOF/TOF plate through Nano‐LC MALDI spotter. Subsequently, fractionated and spotted peptides were identified using MALDI‐TOF/TOF. We identified several E6AP interacting proteins including previously reported such as HSP70 and new ones such as Enolase‐1. We further confirmed that E6AP and Enolase1 interacted and colocalized more in the cytoplasmic periphery in breast cancer cells and further demonstrated that E6AP also targeted ENO1 for ubiquitin‐mediated degradation in these cells. [ABSTRACT FROM AUTHOR]

The present study was aimed at analysing the mid‐oestrous uterine blood flow parameters during varying degree of endometritis in dairy cows. Degree of clinical endometritis was adjudged on the basis of visual examination of uterine discharge collected from cows at mid‐oestrus, that is mild (slightly turbid; n = 13), moderate (turbid with pus flakes; n = 14) and severe (milky; n = 13). Pulsatility and resistance indices (PI and RI), time average mean velocity (TAMEAN), time average maximum velocity (TAMAX), diameter of the artery, volume of blood flow, Doppler pulse duration (DPD) and systolic upstroke/acceleration time (AT) were measured to study the spectral waveforms at mid‐oestrus. Significantly higher (p < .01) PI and RI were found in cows diagnosed with mild degree in comparison with cows diagnosed with moderate and severe degrees of clinical endometritis. There was significantly higher (p < .01) velocity (TAMEAN and TAMAX), volume of blood flow (BFV‐TAMEAN, BFV‐TAMAX) and DPD in both the middle uterine arteries during moderate and severe degrees of clinical endometritis as compared to mild endometritis. However, significantly higher (p < .01) AT was recorded in cows diagnosed with mild degree as compared to moderate and severe degrees of clinical endometritis. Pearson's correlation analysis has shown that RI was positively correlated with PI and AT in all the groups under study (mild degree, r = .72 and.49; moderate degree, r = .54 and.38; severe degree, r = .90 and.42; p < .05). However, there found significantly negative correlation (p < .05) with other parameters in all the cows irrespective of degree of inflammation. Therefore, it may be deducted that assessment of uterine inflammation can be done with a non‐invasive technique known as Doppler sonography which can be useful in adjudging the hemodynamic changes inside uterus and future fertility of dairy cows. [ABSTRACT FROM AUTHOR]

Purpose: Health disparities among LGBTQ people have been documented across various settings and recent research has indicated that many disparities are heightened in the context of rurality. Among these disparities is the decreased rate of primary care utilization by rural LGBTQ individuals. Understanding and addressing provider knowledge and attitudes related to LGBTQ health provides a relevant avenue for addressing underutilization. Methods: The study presented was a mail‐out survey regarding rural primary care providers' knowledge and experiences regarding LGBTQ health. Publicly available records were compiled to recruit a total sample of 113 primary care providers, at a response rate of 19.8%. Findings: A majority of respondents reported experience providing care to LGBTQ patients, while only slightly over half had received LGBTQ health education. Data analyses revealed significant associations between reported experiences and patient characteristics including religion, religiousness, age, length of time practicing in current provider role, and gender identity. Provider knowledge of LGBTQ health varied greatly across the items assessed. Provider profession (physician, nurse practitioner, physician assistant) and length of current county residence were significantly predictive of LGBTQ knowledge scores. Conclusion: Results provide insight into rural health care for LGBTQ people. Preeminent findings were: (1) an existing need for LGBTQ health education, (2) variation in knowledge across content areas, and (3) association between knowledge, profession, and length of current county residence. Promotion of rural LGBTQ health may benefit by addressing identified gaps in current care. [ABSTRACT FROM AUTHOR]

Background Tenofovir disoproxil fumarate ( TDF) is an antiretroviral agent frequently used to treat human immunodeficiency virus ( HIV). There are concerns regarding its potential to cause acute kidney injury, chronic kidney disease, and proximal tubulopathy. Although TDF can effectively suppress HIV after kidney transplantation, it is unknown whether use of TDF-based antiretroviral therapy ( ART) after kidney transplantation adversely affects allograft survival. Methods We examined 104 HIV+ kidney transplant ( KT) recipients at our center between 2001 and 2014. We generated a propensity score for TDF treatment using recipient and donor characteristics. We then fit Cox proportional hazards models to investigate the association between TDF treatment and 3-year, death-censored primary allograft failure, adjusting for the propensity score and delayed graft function ( DGF). Results Of the 104 HIV+ KT candidates who underwent transplantation during the study period, 23 (22%) were maintained on TDF-based ART at the time of transplantation, and 81 (78%) were on non- TDF-based ART. Median age of the cohort was 48 years; 87% were male; 88% were black; and median CD4 count at transplantation was 450 cells/mm3. Median kidney donor risk index was 1.2. At 3 years post transplantation, primary allograft failure occurred in 26% of patients on TDF-based ART and in 28% of patients on non- TDF-based ART ( P=.5). TDF treatment was not associated with primary allograft failure at 3 years post transplant after adjusting for DGF and a propensity score for TDF use (hazard ratio 2.12, 95% confidence interval 0.41-10.9). Conclusions In a large single-center experience of HIV+ kidney transplantation, TDF use following kidney transplantation was not significantly associated with primary allograft failure. These results may help inform management for HIV+ KT recipients in need of TDF therapy for adequate viral suppression. [ABSTRACT FROM AUTHOR]

CCAAT/enhancer‐binding protein α (C/EBPα), a key myeloid transcription factor, drives myeloid differentiation from blast cells by regulating the expression of granulocyte colony stimulating factor receptor and C/EBPε as required for promoting granulocyte differentiation. Here, we show that serine/threonine‐protein kinase NLK, also known as Nemo‐like kinase, physically associates with C/EBPα and phosphorylates it at multiple sites, including Ser21, Thr226, Thr230 and S234, leading to its ubiquitin‐mediated degradation. Individual phospho‐point mutants of C/EBPα could be phosphorylated by NLK, but a mutant with all phosphorylatable residues replaced by alanine resisted phosphorylation and degradation by NLK, as did the single point mutants. Furthermore, although ectopic expression of NLK enhanced phosphorylation of C/EBPα levels, it markedly inhibited total C/EBPα protein levels. Conversely, NLK depletion inhibited endogenous C/EBPα phosphorylation but enhanced its total protein levels in several acute myeloid leukemia (AML) cell lines and in peripheral blood mononuclear cells isolated from number of AML patient samples. Importantly, NLK depletion in peripheral blood mononuclear cells from primary AML patients not only restored C/EBPα protein levels, but also induced myeloid differentiation, suggesting that NLK could be therapeutically targeted to restore C/EBPα to resolve differentiation arrest in AML. [ABSTRACT FROM AUTHOR]

Primary cardiac lymphoma (PCL) is an extremely rare diagnosis. We present a case of a 38-year-old immunocompetent female who presented with dyspnea on exertion and chest pain and the echocardiography revealed a mass in the left atrium (LA) causing moderate mitral regurgitation and mimicking a left atrial myxoma. The patient was managed with excision of the mass and mitral valve replacement followed by chemotherapy. The histopathology revealed B-cell non-Hodgkin lymphoma (NHL) with tumor cells showing immunoreactivity with CD20 and negative for CD45RO., (© 2012 Wiley Periodicals, Inc.)