Covid-19-Associated Mucormycosis: Histopathology of the Deadly Fungal Infection.

Introduction Many patients suffered from rhino-orbital-cerebral mucormycosis during the coronavirus disease 2019 (COVID-19) pandemic in India. Diabetes is a known risk factor of COVID-19 infection and mucormycosis. Objective The present study was done to describe the clinical spectrum and histopathological findings of mucormycosis in COVID-19 patients and their outcomes. Methods A cross-sectional study was done over a period of two and half months. The biopsy samples or scrapings from sinonasal or periorbital tissue of 38 patients were analyzed. Hematoxylin & Eosin (H&E stain) slides were evaluated along with Grocott-Gomori methenamine-silver and Periodic acid-Schiff stains to highlight the fungal elements. Results The male to female ratio was 2.5:1, and the mean age of the subjects was 53 years old. A total of 68.4% ( n = 26/38) of the patients had diabetes as a comorbidity, 84.2% ( n = 32/38) had a history of steroid intake, and 55.3% ( n = 21/38) were given supplemental oxygen during their treatment. The common presentations were nasal blockage, discharge, eye pain, headache, and altered mentation. The sites of biopsy were: nasal cavity 76.3% ( n = 29/38), periorbital fat/orbit 21.1% ( n = 8/38), maxillary sinus 15.8% ( n = 6/38) and ethmoid sinus 13.2% ( n = 5/38). In 76.3% ( n = 29/38) cases, broad, irregular, nonseptate, and right-angle branching hyphae were seen on H&E-stained tissue sections. Conclusion COVID-19 led to various complications in individuals affected by it. Mucormycosis was one such lethal complication. An early diagnosis and prompt treatment is crucial to control the progression of the disease and improve outcomes.

Cardiogenic Shock Intravascular Cooling Trial (CHILL-SHOCK).

BACKGROUND: Cardiogenic shock (CS) is complicated by high mortality rates. Targeted temperature control (TTC) has been proposed as an adjunct therapy in CS. This study aims to examine the safety of TTC in patients presenting with CS. METHODS AND RESULTS: In this open-label, randomized controlled pilot trial, 20 patients with hemodynamic criteria for CS were assigned to standard of care plus TTC vs standard of care alone. The primary outcome was a composite safety outcome, including well-described complications of TTC. Secondary outcomes included mortality at 90 days, invasive hemodynamic and echocardiographic parameters, electrocardiographic measurements, and inotrope dosing. There were no significant differences in the composite analysis of prespecified safety outcomes (3 events in the TTC group vs 0 events in the control group; P = 0.24). Patients randomized to TTC demonstrated a statistically significant increase in cardiac index and cardiac power index compared to the control group at 48-96 hours after randomization (3.6 [3.1, 3.9] L/min/m2 vs 2.6 [2.5, 3.15] L/min/m2; P = 0.029 and 0.61 [0.55, 0.7] W/m2 vs 0.53 [0.435, 0.565] W/m2; P = 0.029, respectively). CONCLUSION: TTC may be a safe adjunct therapy for patients presenting with CS and may yield improvement in specific hemodynamic parameters.

The interplay of rheumatoid arthritis and osteoporosis: exploring the pathogenesis and pharmacological approaches.

Rheumatoid arthritis (RA) and osteoporosis are two chronic disorders that are often seen together. RA is an autoimmune disorder that causes pain and inflammation in the joints, while osteoporosis is a disorder in which the bones become weak and fragile. Risk factors for bone loss in RA include disease activity, longer disease duration, erosive disease, autoantibody positivity, and joint damage leading to impaired physical activity. Recent research has shown that there is a complex interplay between immune cells, cytokines, and bone remodeling processes in both RA and osteoporosis. The bone remodeling process is regulated by cytokines and immune system signaling pathways, with osteoclasts activated through the RANK/RANKL/OPG pathway and the Wnt/DKK1/sclerostin pathway. Understanding these mechanisms can aid in developing targeted therapies for treatment of osteoporosis in RA patients. Current pharmacological approaches include anti-osteoporotic drugs such as bisphosphonates, denosumab, teriparatide, abaloparatide, raloxifene, and romosozumab. Conventional disease-modifying antirheumatic drugs such as methotrexate and biologicals including TNF inhibitors, IL-6 inhibitors, rituximab, and abatacept lower disease activity in RA and can improve bone metabolism by reducing inflammation but have limited impact on bone mineral density. This review will shed light on the relationship between osteoporosis and rheumatoid arthritis as well as the various factors that influence the onset of osteoporosis in RA patients. We also explore several treatment approaches to effectively managing osteoporosis in RA patients.

A novel bioinformatic approach reveals cooperation between Cancer/Testis genes in basal-like breast tumors.

Breast cancer is the most prevalent type of cancer in women worldwide. Within breast tumors, the basal-like subtype has the worst prognosis, prompting the need for new tools to understand, detect, and treat these tumors. Certain germline-restricted genes show aberrant expression in tumors and are known as Cancer/Testis genes; their misexpression has diagnostic and therapeutic applications. Here we designed a new bioinformatic approach to examine Cancer/Testis gene misexpression in breast tumors. We identify several new markers in Luminal and HER-2 positive tumors, some of which predict response to chemotherapy. We then use machine learning to identify the two Cancer/Testis genes most associated with basal-like breast tumors: HORMAD1 and CT83. We show that these genes are expressed by tumor cells and not by the microenvironment, and that they are not expressed by normal breast progenitors; in other words, their activation occurs de novo. We find these genes are epigenetically repressed by DNA methylation, and that their activation upon DNA demethylation is irreversible, providing a memory of past epigenetic disturbances. Simultaneous expression of both genes in breast cells in vitro has a synergistic effect that increases stemness and activates a transcriptional profile also observed in double-positive tumors. Therefore, we reveal a functional cooperation between Cancer/Testis genes in basal breast tumors; these findings have consequences for the understanding, diagnosis, and therapy of the breast tumors with the worst outcomes.

Direct inkjet writing of polylactic acid/ß-tricalcium phosphate composites for bone tissue regeneration: A proof-of-concept study.

There is an ever-evolving need of customized, anatomic-specific grafting materials for bone regeneration. More specifically, biocompatible and osteoconductive materials, that may be configured dynamically to fit and fill defects, through the application of an external stimulus. The objective of this study was to establish a basis for the development of direct inkjet writing (DIW)-based shape memory polymer-ceramic composites for bone tissue regeneration applications and to establish material behavior under thermomechanical loading. Polymer-ceramic (polylactic acid [PLA]/ß-tricalcium phosphate [ß-TCP]) colloidal gels were prepared of different w/w ratios (90/10, 80/20, 70/30, 60/40, and 50/50) through polymer dissolution in acetone (15% w/v). Cytocompatibility was analyzed through Presto Blue assays. Rheological properties of the colloidal gels were measured to determine shear-thinning capabilities. Gels were then extruded through a custom-built DIW printer. Space filling constructs of the gels were printed and subjected to thermomechanical characterization to measure shape fixity (Rf) and shape recovery (Rr) ratios through five successive shape memory cycles. The polymer-ceramic composite gels exhibited shear-thinning capabilities for extrusion through a nozzle for DIW. A significant increase in cellular viability was observed with the addition of ß-TCP particles within the polymer matrix relative to pure PLA. Shape memory effect in the printed constructs was repeatable up to 4 cycles followed by permanent deformation. While further research on scaffold macro-/micro-geometries, and engineered porosities are warranted, this proof-of-concept study suggested suitability of this polymer-ceramic material and the DIW 3D printing workflow for the production of customized, patient specific constructs for bone tissue engineering.

Do Tofacitinib Generics Exhibit Conventional Synthetic Disease-Modifying Anti-rheumatic Drug and Non-steroidal Anti-inflammatory Drug-Sparing Ability in the Management of Axial Spondyloarthritis?

INTRODUCTION: Tofacitinib has emerged as a therapeutic option for axial spondyloarthritis (axSpA) following successful clinical trials. The evidence on the efficacy of tofacitinib generics in the management of axSpA is limited. In India, the usage of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) is commonplace in the management of axSpA. Our primary aim was to identify the csDMARD and non-steroidal anti-inflammatory drug (NSAID)-sparing role of tofacitinib generics in an axSpA population. METHODS: This was a retrospective study in a real-world clinical setting. Data from nine rheumatology centers across India were analyzed for 168 patients with active axSpA who were initiated on generic tofacitinib 5 mg twice daily in conjunction with csDMARDs and NSAIDs, over a duration of six months. Our primary outcome was to evaluate the csDMARD and NSAID-sparing effect of tofacitinib generics, while the secondary outcome assessed safety profiles and efficacy at six months. RESULTS: The median Ankylosing Spondylitis Disease Activity Score (ASDAS) erythrocyte sedimentation rate (ESR) score of the study population was 3.91 (3.26, 4.56). Alongside tofacitinib generics, 121 (72%) patients were co-administered csDMARDs (methotrexate/sulfasalazine/both), and 90 (53.6%) patients were co-administered NSAIDs. The csDMARD, NSAID, and combined csDMARD + NSAID-sparing effects of tofacitinib generics were seen in 85 (50.6%), 156 (92.9%), and 81 (48.2%) patients, respectively. Adverse events were mild and well-tolerated. At six months, 124 (57.9%) patients had attained clinically important improvement in ASDAS ESR score, and the median decrease in ASDAS ESR score was 2.02 (1.18, 2.96). CONCLUSION: This real-world study provides evidence supporting the csDMARD and NSAID-sparing ability of tofacitinib generics in the treatment of axSpA. Tofacitinib generics displayed a good safety profile and showed signals of efficacy as well.

Laparoscopic limited hemicolectomy for descending colo-colic intussusception in an adult.

Intussusception in adults represents 1% of bowel obstructions and up to 0.02% of all hospital admissions. Amongst these, colo-colic intussusception of the descending colon forms the rarest of causes due to the fixed nature of the descending colon. Most of adult intussusceptions follow a lead point and are commonly due to colonic malignancy which may get missed on pre-operative evaluation. Surgery is usually warranted as these patients are usually symptomatic and at risk of vascular compromise, leading to perforations and obscure malignancies. We present a case of laparoscopic limited hemicolectomy and primary anastomosis in a middle-aged male who presented with colo-colic intussusception, which appeared to be following a malignant mass on imaging and lipoma on colonoscopic biopsy done twice. Keeping in mind the possibility of a malignant lead point, no attempt was made to reduce the intussusception and a vessel first approach with 5 cm margin on either side was performed.

Noninvasive assessment of left ventricular end-diastolic pressure using machine learning-derived phasic left atrial strain.

AIMS: While transthoracic echocardiography (TTE) assessment of left ventricular end-diastolic pressure (LVEDP) is critically important, the current paradigm is subject to error and indeterminate classification. Recently, peak left atrial strain (LAS) was found to be associated with LVEDP. We aimed to test the hypothesis that integration of the entire LAS time curve into a single parameter could improve the accuracy of peak LAS in the noninvasive assessment of LVEDP with TTE. METHODS AND RESULTS: We retrospectively identified 294 patients who underwent left heart catheterization and TTE within 24 h. LAS curves were trained using machine learning (100 patients) to detect LVEDP ≥ 15 mmHg, yielding the novel parameter LAS index (LASi). The accuracy of LASi was subsequently validated (194 patients), side by side with peak LAS and ASE/EACVI guidelines, against invasive filling pressures. Within the validation cohort, invasive LVEDP was elevated in 116 (59.8%) patients. The overall accuracy of LASi, peak LAS, and American Society of Echocardiography/European Association for Cardiovascular Imaging (ASE/EACVI) algorithm was 79, 75, and 76%, respectively (excluding 37 patients with indeterminate diastolic function by ASE/EACVI guidelines). When the number of LASi indeterminates (defined by near-zero LASi values) was matched to the ASE/EACVI guidelines (n = 37), the accuracy of LASi improved to 87%. Importantly, among the 37 patients with ASE/EACVI-indeterminate diastolic function, LASi had an accuracy of 81%, compared with 76% for peak LAS. CONCLUSION: LASi allows the detection of elevated LVEDP using invasive measurements as a reference, at least as accurately as peak LAS and current diastolic function guideline algorithm, with the advantage of no indeterminate classifications in patients with measurable LAS.

A genetic screen identifies BEND3 as a regulator of bivalent gene expression and global DNA methylation.

Epigenetic mechanisms are essential to establish and safeguard cellular identities in mammals. They dynamically regulate the expression of genes, transposable elements and higher-order chromatin structures. Consequently, these chromatin marks are indispensable for mammalian development and alterations often lead to disease, such as cancer. Bivalent promoters are especially important during differentiation and development. Here we used a genetic screen to identify new regulators of a bivalent repressed gene. We identify BEND3 as a regulator of hundreds of bivalent promoters, some of which it represses, and some of which it activates. We show that BEND3 is recruited to a CpG-containg consensus site that is present in multiple copies in many bivalent promoters. Besides having direct effect on the promoters it binds, the loss of BEND3 leads to genome-wide gains of DNA methylation, which are especially marked at regions normally protected by the TET enzymes. DNA hydroxymethylation is reduced in Bend3 mutant cells, possibly as consequence of altered gene expression leading to diminished alpha-ketoglutarate production, thus lowering TET activity. Our results clarify the direct and indirect roles of an important chromatin regulator, BEND3, and, more broadly, they shed light on the regulation of bivalent promoters.

Low Serum Levels of Zinc, Selenium, and Vitamin D3 Are Biomarkers of Airway Inflammation and Poor Asthma Control: A Two-Centre Study.

Background Asthma is a chronic inflammatory disease with its control being affected by underlying oxidative stress. Trace elements, along with vitamin D3, play an important role in immune alterations leading to an imbalance of Th1/Th2 helper cells. However, their role in asthma pathogenesis and control is inconsistent and inconclusive. The objective of our study was to assess levels of serum trace elements like zinc, copper, selenium, iron, magnesium, vitamin D3 levels, IgE, and HsCRP in asthmatic children, compare with healthy controls, and assess their association with the level of asthma control. Methods A cross-sectional study was conducted from 2019 to 2021 enrolling 100 asthmatic children and 75 healthy controls. The level of asthma control was assessed as uncontrolled, partly controlled, and controlled asthma as per GINA Guidelines. Mean and standard deviation were calculated for each element and mean differences between groups were analyzed by student t-test. A p-value of <0.05 was considered significant. Results The mean age was 8.75±2.89 yrs in cases and 9.04±2.79 in controls. A total of 57.6% of cases had atopic comorbidities. The mean serum zinc levels were 51±12.8 mg/dl, which was very low in asthmatic children as compared to 60±18.2mg/dl (p-value 0.0002) in healthy controls. Serum selenium was 13±3 µg/dl in asthmatics vs. 15±4 µg/dl (p-value 0.0002) in healthy controls. Serum copper was 115.2±21.92µg/dl vs. 125.3±31.99µg/dl (p-value 0.015), Serum vitamin D3 levels were 13.07±7.82ng/ml vs. 17.82±14.62 ng/ml(p-value 0.006) in both groups, respectively. SIgE and HsCRP were high in asthmatic children suggestive of eosinophilic inflammation. Serum zinc was 49±5.45 mg/dl in the uncontrolled group, 53±6.1 in the partly controlled, and 58±8.0 in the well-controlled group (p<0.0001). Serum selenium was 10± 3.0 µg/dl in the uncontrolled group vs. 13± 2.0 and 14± 2.0 µg/dl in the partly controlled and well-controlled groups, respectively (p-value <0.0001). Vitamin D3 was significantly low (9.32±5.95ng/dl) in the uncontrolled group vs. 12.99±4.97 and 13.40±5.92 ng/dl(p<0.005) in the partly controlled and well-controlled groups respectively. Vitamin D3 showed a strong positive correlation with zinc (r=0.4,p< 0.0001) and a negative correlation with inflammatory markers like SIgE and HsCRP. Conclusion Children with asthma had low zinc, selenium, and vitamin D3 levels, and were associated with airway inflammation and poor asthma control.

A genome-wide screen reveals new regulators of the 2-cell-like cell state.

In mammals, only the zygote and blastomeres of the early embryo are totipotent. This totipotency is mirrored in vitro by mouse '2-cell-like cells' (2CLCs), which appear at low frequency in cultures of embryonic stem cells (ESCs). Because totipotency is not completely understood, we carried out a genome-wide CRISPR knockout screen in mouse ESCs, searching for mutants that reactivate the expression of Dazl, a gene expressed in 2CLCs. Here we report the identification of four mutants that reactivate Dazl and a broader 2-cell-like signature: the E3 ubiquitin ligase adaptor SPOP, the Zinc-Finger transcription factor ZBTB14, MCM3AP, a component of the RNA processing complex TREX-2, and the lysine demethylase KDM5C. All four factors function upstream of DPPA2 and DUX, but not via p53. In addition, SPOP binds DPPA2, and KDM5C interacts with ncPRC1.6 and inhibits 2CLC gene expression in a catalytic-independent manner. These results extend our knowledge of totipotency, a key phase of organismal life.

Comparison of aspartate aminotransferase platelet ratio index score and insulin resistance in type 2 diabetes mellitus with non-alcoholic fatty liver disease.

Objective. Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases characterized by the presence of ectopic fat in the liver and steatosis, which cannot be explained by alcohol consumption. The association between NAFLD and type 2 diabetes mellitus (T2DM) is well established. As liver fibrosis progresses in a patient with NAFLD, insulin resistance (IR) increases and may worsen diabetes control. The aspartate aminotransferase platelet ratio index (APRI) score is a simple and inexpensive bedside marker that can detect liver fibrosis and cirrhosis. Several studies have shown an association between APRI and NAFLD. However, there is a gap in correlation with IR in patients with diabetes. In this study, we sought to correlate IR and NAFLD in diabetes using the APRI score. Methods. This observational hospital-based cross-sectional study was conducted in the Department of General Medicine, one of the tertiary care hospitals in North India, from February 2019 to July 2020. A total of 70 patients were taken for the study. Patients with T2DM, aged >30 years, who had no history of alcohol use and who had or were newly diagnosed with NAFLD were enrolled in the study. Results. Significant differences in mean HbAc1, AST, serum insulin, APRI score and homeo-static model assessment-2 (HOMA2) IR between NAFLD grade 1, grade 2, and grade 3 groups were found. Pearson correlation between APRI score and HOMA2 IR total values revealed a significant positive correlation between them. Conclusions. The data of the present study indicate that the APRI score can be used to assess the IR degree and provide important information for improving glycemic control in T2DM patients with NAFLD.

Algorithmic bias and research integrity; the role of nonhuman authors in shaping scientific knowledge with respect to artificial intelligence: a perspective.

Artificial intelligence technologies were developed to assist authors in bettering the organization and caliber of their published papers, which are both growing in quantity and sophistication. Even though the usage of artificial intelligence tools in particular ChatGPT's natural language processing systems has been shown to be beneficial in research, there are still concerns about accuracy, responsibility, and transparency when it comes to the norms regarding authorship credit and contributions. Genomic algorithms quickly examine large amounts of genetic data to identify potential disease-causing mutations. By analyzing millions of medications for potential therapeutic benefits, they can quickly and relatively economically find novel approaches to treatment. Researchers from several fields can collaborate on difficult tasks with the assistance of nonhuman writers, promoting interdisciplinary research. Sadly, there are a number of significant disadvantages associated with employing nonhuman authors, including the potential for algorithmic prejudice. Biased data may be reinforced by the algorithm since machine learning algorithms can only be as objective as the data they are trained on. It is overdue that scholars bring forth basic moral concerns in the fight against algorithmic prejudice. Overall, even if the use of nonhuman authors has the potential to significantly improve scientific research, it is crucial for scientists to be aware of these drawbacks and take precautions to avoid bias and limits. To provide accurate and objective results, algorithms must be carefully designed and implemented, and researchers need to be mindful of the larger ethical ramifications of their usage.

A Study of Thyroid Profile and Lipid Profile in Patients with Chronic Kidney Disease with or without Hemodialysis in a Tertiary Care Hospital.

BACKGROUND: Chronic kidney disease (CKD), due to increasing frequency and prevalence, has become one of the leading public health issues. The Kidney Disease Outcome Quality Initiative (KDOQI) defines CKD as kidney injury or a reduction in the glomerular filtration rate (GFR) to <60 mL/minute/1.73 m2 for at least 3 months. This study aims to compare the effects of decreased renal function on thyroid profile and lipid profile in CKD patients. MATERIALS AND METHODS: This is a prospective cross-sectional observational study conducted among the patients attending Outpatient Department/Inpatient Department (OPD/IPD) at the School of Medical Sciences & Research, Sharda Hospital, Greater Noida, Uttar Pradesh, India, in known cases of CKD, irrespective of the treatment/stage of CKD. All patients of >18 years of age with CKD were included in the study. RESULT: A total of 200 patients who met the inclusion criteria were included after obtaining detailed informed consent, of which 100 were cases and 100 were controls. The mean age of patients in the study was 47.74 years, with the mean age in patients with CKD 52 years, and the control was 43 years. The mean level of triglycerides (TGs) was significantly higher among the cases, and the high-density lipoprotein (HDL) was significantly lower among cases compared to controls (p < 0.05). Pearson's correlation between thyroid-stimulating hormone (TSH) with creatinine showed a weak albeit significant positive association (r = 0.200; p < 0.05). CONCLUSION: Our study shows a higher incidence of alteration in thyroid profile and dyslipidemia among the patients with CKD compared to controls. There is a necessary need to screen routinely for hypothyroidism and dyslipidemia among patients with CKD. Importantly, thyroid hormone levels and their effects on the progression of CKD have not been studied exhaustively.

Functional constipation: A common and often overlooked cause for abdominal pain in children.

The most common causes for chronic pain abdomen in pediatric practice are functional abdominal pain disorders, a subgroup of functional gastrointestinal disorders under the Rome IV classification. Constipation is usually associated with painful defecation, but abdominal pain as a predominant or presenting symptom of functional constipation (FC) is not very well recognized. We conducted this study to ascertain the prevalence of FC in chronic pain abdomen and proportion of FC children presenting with predominant complaints of pain abdomen. Prevalence of FC and functional abdominal pain was ascertained separately over a 1-year in children > 4 years of age in our hospital. The number of children with FC presenting with abdominal pain was noted. Abdominal pain site and duration were noted in the FC group and were compared with those in the functional abdominal pain group to find out any significance. Diagnosis was based on Rome IV criteria, but relevant investigations to rule out organic pathology were done whenever clinically indicated. The prevalence of abdominal pain was 22% in our gastroenterology service and that of FC was 27%. Among the children presenting with chronic abdominal pain, FC was seen in 10% of the patients and functional abdominal pain disorders in 34%. Among children presenting with constipation, 12% had pain as the sole complaint. However, some form of pain or pain as one of the symptoms was seen in 47.5%.  FC is a major cause for abdomen pain in children and is often overlooked. Not attributing pain to constipation may delay the diagnosis, which may have poor prognosis.

Nuclear Magnetic Resonance-Based Metabolomics Approach Revealed the Intervention Effect of Using Complementary and Alternative Medicine (CAM) by CKD Patients.

Chronic kidney disease (CKD) is the end point of a number of systemic chronic diseases. The prevalence of CKD is increasing worldwide and recent epidemiological studies are showing the high prevalence of renal failure in CKD patients using complementary and alternative medicines (CAMs). Clinicians believe that biochemical profiles of CKD patients using CAM (referred here to as CAM-CKD) may be different compared to those on standard clinical treatment and should be managed differently. The present study aims to explore the potential of the NMR-based metabolomics approach to reveal the serum metabolic disparity between CKD and CAM-CKD patients with respect to normal control (NC) subjects and if the differential metabolic patterns can provide rationale for the efficacy and safety of standard and/or alternative therapies. Serum samples were obtained from 30 CKD patients, 43 CAM-CKD patients, and 47 NC subjects. The quantitative serum metabolic profiles were measured using 1D 1H CPMG NMR experiments performed at 800 MHz NMR spectrometer. The serum metabolic profiles were compared using various multivariate statistical analysis tools available on MetaboAnalyst (freely available web-based software) such as partial least-squares discriminant analysis (PLS-DA) and random forest (a machine learning) classification method. The discriminatory metabolites were identified based on variable importance in projection (VIP) statistics and further evaluated for statistical significance (i.e., p < 0.05) using either Student t-test or ANOVA statistics. PLS-DA models were capable of clustering CKD and CAM-CKD with considerably high values of Q 2 and R 2. Compared to CAM-CKD patients, the sera of CKD patients were characterized by (a) elevated levels of urea, creatinine, citrate, glucose, glycerol, and phenylalanine and phenylalanine-to-tyrosine ratio (PTR) and (b) decreased levels of various amino acids (such leucine, isoleucine, valine, and alanine), high-density lipoproteins, lactate, and acetate. These changes suggested that CKD patients manifest severe oxidative stress, hyperglycemia (with dampened glycolysis), increased protein energy wasting, and reduced lipid/membrane metabolism. Statistically significant and strong positive correlation of PTR with serum creatinine levels suggested the role of oxidative stress in the progression of kidney disease. Significant differences in metabolic patterns between CKD and CAM-CKD patients were observed. With respect to NC subjects, the serum metabolic changes were more aberrant in CKD patients compared to CAM-CKD patients. The aberrant metabolic changes in CKD patients with manifestations of higher oxidative stress compared to CAM-CKD patients could explain clinical discrepancies between CKD and CAM-CKD patients and further advocate the use of different treatment strategies for CKD and CAM-CKD patients.

BK Polyomavirus-Induced Nephropathy in Native Kidney.

BK polyomavirus has been well-studied as an opportunistic infection in immunocompromised kidney transplant patients. In the majority of the population, BK polyomavirus establishes a lifelong infection in renal tubular and uroepithelial cells; however, in an immunocompromised state, the virus can reactivate and can lead to BK polyomavirus-associated nephropathy (BKN). In this case, the patient was a 46-year-old male with a past medical history of HIV, compliant with antiretroviral therapy (ART), and B-cell lymphoma treated with chemotherapy. The patient presented with worsening kidney function of unknown etiology. This prompted further assessment with a kidney biopsy. Kidney biopsy findings were consistent with BKN. In the literature, BKN has been studied in renal transplant patients; however, it rarely involves native kidneys.

Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A.

The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56α is a human tumour suppressor. However, the molecular mechanisms inhibiting PP2A-B56α in cancer are poorly understood. Here, we report molecular level details and structural mechanisms of PP2A-B56α inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56α trimer, CIP2A displaces the PP2A-A subunit and thereby hijacks both the B56α, and the catalytic PP2Ac subunit to form a CIP2A-B56α-PP2Ac pseudotrimer. Further, CIP2A competes with B56α substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56α. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56α stabilizes CIP2A protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation, and abrogated triple-negative breast cancer in vivo tumour growth. Collectively, we discover a unique multi-step hijack and mute protein complex regulation mechanism resulting in tumour suppressor PP2A-B56α inhibition. Further, the results unfold a structural determinant for the oncogenic activity of CIP2A, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases.

PP2A methylesterase PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers.

While organ-confined prostate cancer (PCa) is mostly therapeutically manageable, metastatic progression of PCa remains an unmet clinical challenge. Resistance to anoikis, a form of cell death initiated by cell detachment from the surrounding extracellular matrix, is one of the cellular processes critical for PCa progression towards aggressive disease. Therefore, further understanding of anoikis regulation in PCa might provide therapeutic opportunities. Here, we discover that PCa tumours with concomitant inhibition of two tumour suppressor phosphatases, PP2A and PTEN, are particularly aggressive, having < 50% 5-year secondary-therapy-free patient survival. Functionally, overexpression of PME-1, a methylesterase for the catalytic PP2A-C subunit, inhibits anoikis in PTEN-deficient PCa cells. In vivo, PME-1 inhibition increased apoptosis in in ovo PCa tumour xenografts, and attenuated PCa cell survival in zebrafish circulation. Molecularly, PME-1-deficient PC3 cells display increased trimethylation at lysines 9 and 27 of histone H3 (H3K9me3 and H3K27me3), a phenotype known to correlate with increased apoptosis sensitivity. In summary, our results demonstrate that PME-1 supports anoikis resistance in PTEN-deficient PCa cells. Clinically, these results identify PME-1 as a candidate biomarker for a subset of particularly aggressive PTEN-deficient PCa.