Racial disparity in prostate cancer: an outlook in genetic and molecular landscape.

Prostate cancer (PCa) incidence, morbidity, and mortality rates are significantly impacted by racial disparities. Despite innovative therapeutic approaches and advancements in prevention, men of African American (AA) ancestry are at a higher risk of developing PCa and have a more aggressive and metastatic form of the disease at the time of initial PCa diagnosis than other races. Research on PCa has underlined the biological and molecular basis of racial disparity and emphasized the genetic aspect as the fundamental component of racial inequality. Furthermore, the lower enrollment rate, limited access to national-level cancer facilities, and deferred treatment of AA men and other minorities are hurdles in improving the outcomes of PCa patients. This review provides the most up-to-date information on various biological and molecular contributing factors, such as the single nucleotide polymorphisms (SNPs), mutational spectrum, altered chromosomal loci, differential gene expression, transcriptome analysis, epigenetic factors, tumor microenvironment (TME), and immune modulation of PCa racial disparities. This review also highlights future research avenues to explore the underlying biological factors contributing to PCa disparities, particularly in men of African ancestry.

Current insights into epigenetics, noncoding RNA interactome and clinical pharmacokinetics of dietary polyphenols in cancer chemoprevention.

Several studies have reported the health-beneficial effects of dietary phytochemicals, namely polyphenols, to prevent various diseases, including cancer. Polyphenols, like (-)-epigallocatechin-3-gallate (EGCG) from green tea, curcumin from turmeric, and ellagic acid from pomegranate are known to act by modulating antioxidant, anti-inflammatory and apoptotic signal transduction pathways in the tumor milieu. The evolving literature underscores the role of epigenetic regulation of genes associated with cancer by these polyphenols, primarily via non-coding RNAs (ncRNAs), such as microRNAs (miRNA) and long noncoding RNA (lncRNA). However, there is little clarity on the exact role(s) played by these ncRNAs and their interactions with other ncRNAs, or with their protein targets, in response to modulation by these dietary polyphenols. Here, we review ncRNA interactions and functional networks of the complex ncRNA interactome with their targets in preclinical studies along with the role of epigenetics as well as key aspects of pharmacokinetics and phytochemistry of dietary polyphenols. We also summarize the current state of clinical trials with these dietary polyphenols. Taken together, this synthetic review provides insights into the molecular aspects underlying the anticancer chemopreventive effects of dietary polyphenols as well as summarizes data on novel biomarkers modulated by these polyphenols for preventive or therapeutic purposes in various types of cancer.

Association between Expression of Connective Tissue Genes and Prostate Cancer Growth and Progression.

To find an association between genomic features of connective tissue and pejorative clinical outcomes on radical prostatectomy specimens. We performed a retrospective analysis of patients who underwent radical prostatectomy and underwent a Decipher transcriptomic test for localized prostate cancer in our institution (n = 695). The expression results of selected connective tissue genes were analyzed after multiple t tests, revealing significant differences in the transcriptomic expression (over- or under-expression). We investigated the association between transcript results and clinical features such as extra-capsular extension (ECE), clinically significant cancer, lymph node (LN) invasion and early biochemical recurrence (eBCR), defined as earlier than 3 years after surgery). The Cancer Genome Atlas (TCGA) was used to evaluate the prognostic role of genes on progression-free survival (PFS) and overall survival (OS). Out of 528 patients, we found that 189 had ECE and 27 had LN invasion. The Decipher score was higher in patients with ECE, LN invasion, and eBCR. Our gene selection microarray analysis showed an overexpression in both ECE and LN invasion, and in clinically significant cancer for COL1A1, COL1A2, COL3A1, LUM, VCAN, FN1, AEBP1, ASPN, TIMP1, TIMP3, BGN, and underexpression in FMOD and FLNA. In the TCGA population, overexpression of these genes was correlated with worse PFS. Significant co-occurrence of these genes was observed. When presenting overexpression of our gene selection, the 5-year PFS rate was 53% vs. 68% (p = 0.0315). Transcriptomic overexpression of connective tissue genes correlated to worse clinical features, such as ECE, clinically significant cancer and BCR, identifying the potential prognostic value of the gene signature of the connective tissue in prostate cancer. TCGAp cohort analysis showed a worse PFS in case of overexpression of the connective tissue genes.

Incidence and predictors of poor functional outcome despite complete recanalisation following endovascular thrombectomy for acute ischaemic stroke.

BACKGROUND: Numerous ischaemic stroke patients experience poor functional outcome despite successful recanalisation following endovascular thrombectomy (EVT). We aimed to identify the incidence and predictors of futile complete recanalisation (FCR) in a national stroke registry. METHODS: Patients who achieved complete recanalisation (mTICI 3) following EVT, between October 2015 and March 2020, were included from a United Kingdom national stroke registry. Modified Rankin Scale of 4-6 at discharge was defined as a 'poor/futile outcome'. Backward stepwise multivariable logistic regression analysis was performed with FCR as the dependent variable, incorporating all baseline characteristics, procedural time metrics and post-procedural events. RESULTS: We included 2132 of 4383 patients (48.8%) with complete recanalisation post-EVT, of which 948 patients (44.4%) developed FCR. Following multivariable regression analysis adjusted for potential confounders, patients with FCR were associated with multiple baseline patient, imaging and procedural factors: age (p=0.0001), admission NIHSS scores (p=0.0001), pre-stroke disability (p=0.007), onset-to-puncture (p=0.0001) and procedural times (p=0.0001), presence of diabetes (p=0.005), and use of general anaesthesia (p=0.0001). Although not predictive of outcome, post-procedural events including development of any intracranial haemorrhage (ICH) (p=0.0001), symptomatic ICH (sICH) (p=0.0001) and early neurological deterioration (END) (p=0.007) were associated with FCR. CONCLUSION: Nearly half of patients in this national registry experienced FCR following EVT. Significant predictors of FCR included increasing age, admission NIHSS scores, pre-stroke disability, onset-to-puncture and procedural times, presence of diabetes, atrial fibrillation, and use of general anaesthesia. Post procedural development of any ICH, sICH, and END were associated with FCR.

An Audit of Extrahepatic Portal Vein Obstruction: Experience from Tertiary Referral Center.

BACKGROUND: Extrahepatic portal vein obstruction (EHPVO) is a common cause of portal hypertension in India. AIMS: (1) To evaluate the clinical presentation and the natural history of EHPVO; (2) to describe the risk factors, rebleeding rates and development of portal biliopathy on follow-up; and requirement of surgery in EHPVO at a tertiary care center. METHODS: Data from 318 consecutive patients with EHPVO from June 2012 to October 2020 were analyzed. All patients underwent liver biochemistry, ultrasonography (USG) abdomen, upper gastrointestinal (GI) endoscopy, and viral serology. Color Doppler, computed tomography (CT) abdomen and magnetic resonance cholangiopancreatography (MRCP) were done as indicated. RESULTS: Mean age of presentation was 15.08 years [standard deviation (SD) 12.74; 6 months-60 years; 210 males)]. The presenting features were upper GI bleed (n = 227) (age at first bleed 11 years; 4 months-56 years), left hypochondrium pain or lump (n = 67), and only lower GI bleed (n = 1). Incidentally detected EHPVO on USG was seen in 10.69% (n = 34) patients. Postbleed ascites were seen in 10.69% (n = 34) patients. Six patients had symptomatic portal biliopathy and 14 had hypersplenism. Around 14.77% (n = 47) of patients had a history of being delivered at home, while 3.45% (n = 11) had a history of umbilical sepsis. During follow-up, 35.3% (n = 82) of patients had rebled. On imaging, associated splenic vein (SV) collaterals and superior mesenteric vein (SMV) collaterals were seen in 35.84% (n = 114) and 11.01% (n = 35) patients, respectively. Gallbladder varices were seen in 44.3% (n = 106), while gallstones in 5.66% (n = 18). On endoscopy, 87.42% (n = 278) patients had esophageal varices, 18.86% (n = 60) had isolated fundic varices, and three had ectopic varices. Only two patients had rectal varices and colopathy. Emergency devascularization was required in 3.45% (n = 14) patients for the failure of variceal bleed control, 1.88% (n = 7) underwent splenectomy, and four patients had proximal splenorenal shunt (PSRS) surgery. CONCLUSION: Extrahepatic portal hypertension (EHPVO) is an important cause of portal hypertension (PHT) in our country. The majority of them present with GI bleed; postbleed ascites were seen only in ~10%. Rebleed occurs in one-third of cases. Gallbladder varices were common; portal biliopathy occurred in 10% and were usually asymptomatic.

A case of giant colonic lipoma removed endoscopically using a modified hybrid technique.

Colonic lipomas are benign adipose tumors and are mostly asymptomatic. They may cause symptoms when their size becomes more than 2 cm. Giant colonic lipoma (GCL) is a rare finding in endoscopy which presents with or without macroscopic ulceration and may lead to iron deficiency anaemia (IDA). The choice of treatment of symptomatic large colonic lipomas has been controversial. Here we are presenting a case of GCL presenting with occult bleeding causing iron deficiency anaemia (IDA). It was removed endoscopically using a combination of noradrenaline, endoloop ligation, and snare cautery technique (modified hybrid technique). Successful removal of the GCL lead to the resolution of IDA. This case report highlights that even GCL can be removed endoscopically, thus surgery can be prevented. Clinical Significance: GCL is an unusual cause of anemia. Modified hybrid endoscopic removal technique improves safety.

Perfusion Imaging for Endovascular Thrombectomy in Acute Ischemic Stroke Is Associated With Improved Functional Outcomes in the Early and Late Time Windows.

BACKGROUND: The impact on clinical outcomes of patient selection using perfusion imaging for endovascular thrombectomy (EVT) in patients with acute ischemic stroke presenting beyond 6 hours from onset remains undetermined in routine clinical practice. METHODS: Patients from a national stroke registry that underwent EVT selected with or without perfusion imaging (noncontrast computed tomography/computed tomography angiography) in the early (<6 hours) and late (6-24 hours) time windows, between October 2015 and March 2020, were compared. The primary outcome was the ordinal shift in the modified Rankin Scale score at hospital discharge. Other outcomes included functional independence (modified Rankin Scale score ≤2) and in-hospital mortality, symptomatic intracerebral hemorrhage, successful reperfusion (Thrombolysis in Cerebral Infarction score 2b-3), early neurological deterioration, futile recanalization (modified Rankin Scale score 4-6 despite successful reperfusion) and procedural time metrics. Multivariable analyses were performed, adjusted for age, sex, baseline stroke severity, prestroke disability, intravenous thrombolysis, mode of anesthesia (Model 1) and including EVT technique, balloon guide catheter, and center (Model 2). RESULTS: We included 4249 patients, 3203 in the early window (593 with perfusion versus 2610 without perfusion) and 1046 in the late window (378 with perfusion versus 668 without perfusion). Within the late window, patients with perfusion imaging had a shift towards better functional outcome at discharge compared with those without perfusion imaging (adjusted common odds ratio [OR], 1.45 [95% CI, 1.16-1.83]; P=0.001). There was no significant difference in functional independence (29.3% with perfusion versus 24.8% without; P=0.210) or in the safety outcome measures of symptomatic intracerebral hemorrhage (P=0.53) and in-hospital mortality (10.6% with perfusion versus 14.3% without; P=0.053). In the early time window, patients with perfusion imaging had significantly improved odds of functional outcome (adjusted common OR, 1.51 [95% CI, 1.28-1.78]; P=0.0001) and functional independence (41.6% versus 33.6%, adjusted OR, 1.31 [95% CI, 1.08-1.59]; P=0.006). Perfusion imaging was associated with lower odds of futile recanalization in both time windows (late: adjusted OR, 0.70 [95% CI, 0.50-0.97]; P=0.034; early: adjusted OR, 0.80 [95% CI, 0.65-0.99]; P=0.047). CONCLUSIONS: In this real-world study, acquisition of perfusion imaging for EVT was associated with improvement in functional disability in the early and late time windows compared with nonperfusion neuroimaging. These indirect comparisons should be interpreted with caution while awaiting confirmatory data from prospective randomized trials.

Why do African-American men face higher risks for lethal prostate cancer?

PURPOSE OF REVIEW: African-American men in the USA have a higher incidence of and mortality from prostate cancer (PCa), with a longstanding debate about the cause for these worse outcomes. This review examines differences in tumour biology and socioeconomics for African-American and Non-Hispanic White (NHW) men to answer the question 'why AA men face higher risks for lethal PCa' and draw a management consensus to redress the imbalance. RECENT FINDINGS: Recent evidence from over the past 2 years suggests the reasons why African-American men face a higher risk of lethal PCa are multifactorial, with contributions from differences in tumour biology as well as socioeconomic and healthcare access factors. Regarding tumour biology, genomic and transcriptome profiling suggests African-American men have upregulated expression of genes related to inflammatory pathways with downregulation of DNA repair genes. In contrast, NHW men have higher DNA repair pathways and metabolic pathways involving glycolysis and cell cycle activity. In addition, epidemiological evidence suggests equal healthcare access ensures equal PCa specific outcomes, implying African-American men's disease is not inherently more lethal. However, differences in tumour biology remain, which may explain specific differences in PCa incidence and the clinical findings of African-American men's increased response to immunotherapy and radiotherapy in recent trials. SUMMARY: Regardless of racial differences in disease outcomes and the factors causing them, African-American and NHW men seem to have diseases unique to their ancestry. This supports the exploration of personalized PCa treatment approaches, leveraging translational basic science research to uncover these differences and devise specific individualized methods therapeutic regimes to address them.

A core chromatin remodeling factor instructs global chromatin signaling through multivalent reading of nucleosome codes.

ATP-dependent NuRD repressor complexes involve combinatorial assembly of its subunits. However, the mechanism of gene transcription by MTA1/NuRD remains enigmatic. Here we report that MTA1 methylation by G9a methytransferase and demethylation by LSD1 determines the nucleosome remodeling and transcriptional outcome. Contrary to the current static repressor model of the NuRD complex, we discovered that MTA1 association with nucleosomes and corepressor/coactivator complexes is dynamic. While methylated MTA1 is required for the NuRD repressor complex, demethylated MTA1 recognizes the bivalent histone H3K4-AcK9 mark and recruits coactivator NURF-trithorax remodeling complex in a signaling-dependent manner. MTA1's lysine 532 methylation represents a molecular switch as methylated and demethylated MTA1 nucleate NuRD or NURF complexes with opposite functions in a cyclical manner. In addition, MTA1 possesses an inherent histone amplifier activity with an instructive role in impacting the epigenetic landscape, providing a new perspective to the molecular governance of dual coregulator functions of a master coregulator.

Thiopurine-induced Myelosuppression with Severe Sepsis in a Patient with Crohn's Disease: A Case Report.

Thiopurines by their glucocorticoid-sparing property help in maintaining remission for patients with inflammatory bowel disease (IBD), when glucocorticoids are reduced and withdrawn. However, due to bone marrow suppression, it cannot be used in various conditions where it is indicated. A 17-year-old patient presented with pancytopenia with neutropenic sepsis and alopecia after 3 weeks of starting azathioprine for her underlying Crohn's disease. Thiopurine S-methyltransferase (TPMT;*2, *3A, *3C) analysis resulted in a wild-type genotype, whereas homozygous Nudix hydrolase 15 (NUDT 15 C415T) variant was positive. Azathioprine was stopped immediately, and she was started on broad-spectrum antibiotics that led to some clinical improvements initially, but later on, the patient developed intestinal obstruction along with postoperative complications leading to death. In this report, we highlight a case of serious hematological toxicity associated with azathioprine use in a patient with Crohn's disease with homozygous NUDT 15 variant, thus favoring the implementation of a pharmacogenomic approach before starting azathioprine, particularly in the Asian population. HOW TO CITE THIS ARTICLE: Debnath P, Nair S, Jain S, Udgirkar S, Contractor Q, Rathi P. Thiopurine-induced Myelosuppression with Severe Sepsis in a Patient with Crohn's Disease: A Case Report. Indian J Crit Care Med 2021;25(2):228-230. PRIOR PRESENTATION OF CASE REPORT AT PROFESSIONAL MEETING: The case was presented in abstract form at the American College of Gastroenterology Annual Scientific Meeting, held at San Antonio, TX, USA 2019. INFORMED CONSENT FOR PUBLICATION OF CASE DETAILS: Obtained from patient's relatives.

Prediction of biochemical recurrence in prostate cancer patients who underwent prostatectomy using routine clinical prostate multiparametric MRI and decipher genomic score.

BACKGROUND: Biochemical recurrence (BCR) affects a significant proportion of patients who undergo robotic-assisted laparoscopic prostatectomy (RALP). PURPOSE: To evaluate the performance of a routine clinical prostate multiparametric magnetic resonance imaging (mpMRI) and Decipher genomic classifier score for prediction of biochemical recurrence in patients who underwent RALP. STUDY TYPE: Retrospective cohort study. SUBJECTS: Ninety-one patients who underwent RALP performed by a single surgeon, had mpMRI before RALP, Decipher taken from RALP samples, and prostate specific antigen (PSA) follow-up for >3 years or BCR within 3 years, defined as PSA >0.2 mg/ml. FIELD STRENGTH/SEQUENCE: mpMRI was performed at 27 different institutions using 1.5T (n = 10) or 3T scanners and included T2 w, diffusion-weighted imaging (DWI), or dynamic contrast-enhanced (DCE) MRI. ASSESSMENT: All mpMRI studies were reported by one reader using Prostate Imaging Reporting and Data System v. 2.1 (PI-RADsv2.1) without knowledge of other findings. Eighteen (20%) randomly selected cases were re-reported by reader B to evaluate interreader variability. STATISTICAL TESTS: Univariate and multivariate analysis using greedy feature selection and tournament leave-pair-out cross-validation (TLPOCV) were used to evaluate the performance of various variables for prediction of BCR, which included clinical (three), systematic biopsy (three), surgical (six: RALP Gleason Grade Group [GGG], extracapsular extension, seminal vesicle invasion, intraoperative surgical margins [PSM], final PSM, pTNM), Decipher (two: Decipher score, Decipher risk category), and mpMRI (eight: prostate volume, PSA density, PI-RADv2.1 score, MRI largest lesion size, summed MRI lesions' volume and relative volume [MRI-lesion-percentage], mpMRI ECE, mpMRI seminal vesicle invasion [SVI]) variables. The evaluation metric was the area under the curve (AUC). RESULTS: Forty-eight (53%) patients developed BCR. The best-performing individual features with TLPOCV AUC of 0.73 (95% confidence interval [CI] 0.64-0.82) were RALP GGG, MRI-lesion-percentage followed by biopsy GGG (0.72, 0.62-0.82), and Decipher score (0.71, 0.60-0.82). The best performance was achieved by feature selection of Decipher+Surgery and MRI + Surgery variables with TLPOCV AUC of 0.82 and 0.81, respectively DATA CONCLUSION: Relative lesion volume measured on a routine clinical mpMRI failed to outperform Decipher score in BCR prediction. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:1075-1085.

Combining alpha radiation-based brachytherapy with immunomodulators promotes complete tumor regression in mice via tumor-specific long-term immune response.

Diffusing alpha-emitters radiation therapy (DaRT) is the only known method for treating solid tumors with highly destructive alpha radiation. More importantly, as a monotherapy, DaRT has been shown to induce a systemic antitumor immune response following tumor ablation. Here, immunomodulatory strategies to boost the antitumor immune response induced by DaRT, and the response specificity, were investigated in the colon cancer CT26 mouse model. Local treatment prior to DaRT, with the TLR3 agonist poly I:C, was sufficient to inhibit tumor growth relative to poly I:C or DaRT alone. DaRT used in combination with the TLR9 agonist CpG, or with the TLR1/2 agonist XS15 retarded tumor growth and increased tumor-rejection rates, compared to DaRT alone, curing 41% and 20% of the mice, respectively. DaRT in combination with CpG, the Treg inhibitor cyclophosphamide, and the MDSC inhibitor sildenafil, cured 51% of the animals, compared to only 6% and 0% cure when immunomodulation or DaRT was used alone, respectively. Challenge and Winn assays revealed that these high cure rates involved a specific immunological memory against CT26 antigens. We suggest that DaRT acts in synergy with immunomodulation to induce a specific and systemic antitumor immune response. This strategy may serve as a safe and efficient method not only for tumor ablation, but also for in situ vaccination of cancer patients.

A transcriptomic signature of tertiary Gleason 5 predicts worse clinicopathological outcome.

OBJECTIVE: To investigate the genomic features of tertiary pattern 5 (TP5) on radical prostatectomy specimens in an effort to explain the poor clinical outcomes associated with this disease subtype. PATIENTS AND METHODS: Data from 159 men with Gleason Grade Group (GGG) 3 or 4 were considered. All patients had Decipher diagnostic testing with transcript profiles and single-channel array normalisation (SCAN)-normalised expression of coding genes. The relationship between Decipher and TP5 was investigated by linear and binary logistic regressions. A differential transcriptomic analysis between patients with and without TP5 was performed. The prognostic role of these genes on progression-free survival (PFS) and overall survival (OS) was evaluated using The Cancer Genome Atlas. RESULTS: In all, 52/159 (33%) patients had GGG 3-4 with TP5 disease. TP5 was associated with a higher Decipher score (ß 0.07, 95% confidence interval [CI] 0.02-0.13; P = 0.04) and higher likelihood of falling within the intermediate- or high-risk categories (odds ratio 3.34, 95% CI 1.34-8.35; P = 0.01). Analysis of microarray data revealed an 18-gene signature that was differentially expressed in patients with TP5; 13 genes were over- and five under-expressed in the TP5 cohort. The overexpression of cyclin dependent kinase inhibitor 2B (CDKN2B), polo-like kinase 1 (PLK1), or cell division cycle 20 (CDC20) was associated with worse PFS. The group harbouring overexpression of at least one gene had a 5-year PFS rate of 50% vs 74% in the group without overexpression (P < 0.001). CONCLUSIONS: Our studies have elucidated unique genomic features of TP5, whilst confirming previous clinical findings that patients harbouring TP5 tend to have worse prognosis. This is the first RNA-based study to investigate the molecular diversity of TP5 and the first correlating CDKN2B to poorer prognosis in patients with prostate cancer.

Multiparametric Magnetic Resonance Imaging Features Identify Aggressive Prostate Cancer at the Phenotypic and Transcriptomic Level.

PURPOSE: Multiparametric magnetic resonance imaging is a diagnostic tool for prostate cancer with limited data on prognostic use. We sought to determine whether multiparametric magnetic resonance could predict aggressive prostate cancer features. MATERIALS AND METHODS: We retrospectively analyzed the records of 206 patients who underwent radical prostatectomy between 2013 and 2017. All patients had available RNA expression data on the final pathology specimen obtained from a location corresponding to a lesion location on multiparametric magnetic resonance imaging. The association between the PIRADS™ (Prostate Imaging Reporting and Data System) score and adverse pathology features were analyzed. We also performed differential transcriptomic analysis between the PIRADS groups. Factors associated with adverse pathology were analyzed using a multivariable logistic regression model. RESULTS: Lesion size (p = 0.03), PIRADS score (p = 0.02) and extraprostatic extension (p = 0.01) associated significantly with the Decipher® score. Multivariable analysis showed that the PIRADS score (referent PIRADS 3, OR 8.1, 95% CI 1.2-57.5, p = 0.04), the Gleason Grade Group (referent 3, OR 5.6, 95% CI 1.5-21.1, p = 0.01) and prostate specific antigen (OR 1.103, 95% CI 1.011-1.203) were risk factors for adverse pathology findings. The difference between PIRADS 4 and 5 did not reach significance (OR 1.9, 95% CI 0.8-4.5, p = 0.12). However, the PI3K-AKT-mTOR, WNT-ß and E2F signaling pathways were more active in PIRADS 5 than in PIRADS 4 cases. CONCLUSIONS: The PIRADS score is associated with adverse pathology results, increased metastatic risk and differential genomic pathway activation.

Imaging in neurocysticercosis.

Neurocysticercosis is a parasitic neurological infection caused by the ingestion of larvae from the adult tapeworm Taenia solium. We describe a man who presented with generalised tonic-clonic seizures. He had been previously diagnosed with epilepsy in Malawi, where he had emigrated from 2 years before this episode. An MRI was performed to further investigate the cause of his seizures, as no previous imaging had been performed. His initial MRI showed multiple characteristic cystic lesions in keeping with neurocysticercosis.

Emerging Vistas for the Nutraceutical Withania somnifera in Inflammaging.

Inflammaging, a coexistence of inflammation and aging, is a persistent, systemic, low-grade inflammation seen in the geriatric population. Various natural compounds have been greatly explored for their potential role in preventing and treating inflammaging. Withania somnifera has been used for thousands of years in traditional medicine as a nutraceutical for its numerous health benefits including regenerative and adaptogenic effects. Recent preclinical and clinical studies on the role of Withania somnifera and its active compounds in treating aging, inflammation, and oxidative stress have shown promise for its use in healthy aging. We discuss the chemistry of Withania somnifera, the etiology of inflammaging and the protective role(s) of Withania somnifera in inflammaging in key organ systems including brain, lung, kidney, and liver as well as the mechanistic underpinning of these effects. Furthermore, we elucidate the beneficial effects of Withania somnifera in oxidative stress/DNA damage, immunomodulation, COVID-19, and the microbiome. We also delineate a putative protein-protein interaction network of key biomarkers modulated by Withania somnifera in inflammaging. In addition, we review the safety/potential toxicity of Withania somnifera as well as global clinical trials on Withania somnifera. Taken together, this is a synthetic review on the beneficial effects of Withania somnifera in inflammaging and highlights the potential of Withania somnifera in improving the health-related quality of life (HRQoL) in the aging population worldwide.

Current insights into transcriptional role(s) for the nutraceutical Withania somnifera in inflammation and aging.

The health-beneficial effects of nutraceuticals in various diseases have received enhanced attention in recent years. Aging is a continuous process wherein physiological activity of an individual declines over time and is characterized by various indefinite hallmarks which contribute toward aging-related comorbidities in an individual which include many neurodegenerative diseases, cardiac problems, diabetes, bone-degeneration, and cancer. Cellular senescence is a homeostatic biological process that has an important function in driving aging. Currently, a growing body of evidence substantiates the connection between epigenetic modifications and the aging process, along with aging-related diseases. These modifications are now being recognized as promising targets for emerging therapeutic interventions. Considering that almost all the biological processes are modulated by RNAs, numerous RNA-binding proteins have been found to be linked to aging and age-related complexities. Currently, studies have shed light on the ability of the nutraceutical Withania somnifera (Ashwagandha) to influence RNA expression, stability, and processing, offering insights into its mechanisms of action. By targeting RNA-related pathways, Withania somnifera may exhibit promising effects in ameliorating age-associated molecular changes, which include modifications in gene expression and signaling networks. This review summarizes the potential role of Withania somnifera as a nutraceutical in modulating RNA-level changes associated with aging, encompassing both in vitro and in vivo studies. Taken together, the putative role(s) of Withania in modulation of key RNAs will provide insights into understanding the aging process and facilitate the development of various preventive and therapeutic strategies employing nutraceuticals for healthy aging.

A comparative study of uncomplicated acute non-A-E hepatitis with acute viral hepatitis and acute onset autoimmune hepatitis.

BACKGROUND AND AIMS: Non-A-E hepatitis (NAEH) not leading to acute liver failure (ALF) is poorly documented. The objective was to compare clinical and laboratory features of uncomplicated acute NAEH with acute viral (AVH) and autoimmune hepatitis (AIH) and histopathology in NAEH and AIH. METHODS: Cases of hepatocellular jaundice were included. These were grouped into AVH, AIH and NAEH based on clinical, laboratory and, when indicated, liver biopsy findings. NAEH and AIH were followed up at three months. RESULTS: Of 336 patients with hepatocellular jaundice, 15 (5%) were NAEH, 25 (7%) acute AIH and 45 (14%) AVH. Among NAEH patients, seven (46.7%) were males with a mean age of presentation 39 years. Jaundice (100%) was the most common presentation of NAEH. Peak bilirubin was 10.7 mg/dL. Peak aspartate and alanine aminotransferase (AST, ALT) were 512 and 670 U/L. Five (33.3%) patients had positive anti-nuclear antibody and one had anti-smooth muscle antibody. Mean immunoglobulin G (IgG) levels were 1829. On liver biopsy, all had ballooning degeneration, four (26.7%) had mild and three (20%) moderate interface hepatitis, four (26.7%) mild lymphoplasmacytic infiltrate, one (6.7%) rosette formation, bridging necrosis in none and stage 1 fibrosis in one. Comparing NAEH with AIH, AIH showed significantly older age at presentation, female predisposition, past history of jaundice, lower ALT, more autoantibodies, higher IgG, higher grade interface hepatitis, lymphoplasmacytic infiltrate, rosette formation and higher bilirubin, AST at three months. NAEH and viral hepatitis had similar features. CONCLUSION: Etiology of NAEH is unlikely to be autoimmune and is probably viral, unidentified as yet. Uncomplicated NAEH likely has self-limiting course even without specific treatment.

CD8+ T cell targeting of tumor antigens presented by HLA-E.

The nonpolymorphic major histocompatibility complex E (MHC-E) molecule is up-regulated on many cancer cells, thus contributing to immune evasion by engaging inhibitory NKG2A/CD94 receptors on NK cells and tumor-infiltrating T cells. To investigate whether MHC-E expression by cancer cells can be targeted for MHC-E-restricted T cell control, we immunized rhesus macaques (RM) with rhesus cytomegalovirus (RhCMV) vectors genetically programmed to elicit MHC-E-restricted CD8+ T cells and to express established tumor-associated antigens (TAAs) including prostatic acidic phosphatase (PAP), Wilms tumor-1 protein, or Mesothelin. T cell responses to all three tumor antigens were comparable to viral antigen-specific responses with respect to frequency, duration, phenotype, epitope density, and MHC restriction. Thus, CMV-vectored cancer vaccines can bypass central tolerance by eliciting T cells to noncanonical epitopes. We further demonstrate that PAP-specific, MHC-E-restricted CD8+ T cells from RhCMV/PAP-immunized RM respond to PAP-expressing HLA-E+ prostate cancer cells, suggesting that the HLA-E/NKG2A immune checkpoint can be exploited for CD8+ T cell-based immunotherapies.

Safety and efficacy of adjunctive intra-arterial antithrombotic therapy during endovascular thrombectomy for acute ischemic stroke: a systematic review and meta-analysis.

BACKGROUND: Half of patients who achieve successful recanalization following endovascular thrombectomy (EVT) for acute ischemic stroke experience poor functional outcome. We aim to investigate whether the use of adjunctive intra-arterial antithrombotic therapy (AAT) during EVT is safe and efficacious compared with standard therapy (ST) of EVT with or without prior intravenous thrombolysis. METHODS: Electronic databases were searched (PubMed/MEDLINE, Embase, Cochrane Library) from 2010 until October 2023. Data were pooled using a random-effects model and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk of bias was assessed using ROBINS-I and ROB-2. The primary outcome was functional independence (modified Rankin Scale (mRS) 0-2) at 3 months. Secondary outcomes were successful recanalization (modified Thrombolysis In Cerebral Infarction (TICI) 2b-3), symptomatic intracranial hemorrhage (sICH), and 90-day mortality. RESULTS: 41 randomized and non-randomized studies met the eligibility criteria. Overall, 15 316 patients were included; 3296 patients were treated with AAT during EVT and 12 020 were treated with ST alone. Compared with ST, patients treated with AAT demonstrated higher odds of functional independence (46.5% AAT vs 42.6% ST; OR 1.22, 95% CI 1.07 to 1.40, P=0.004, I2=48%) and a lower likelihood of 90-day mortality (OR 0.71, 95% CI 0.61 to 0.83, P<0.0001, I2=20%). The rates of sICH (OR 1.00, 95% CI 0.82 to 1.22,P=0.97, I2=13%) and successful recanalization (OR 1.09, 95% CI 0.84 to 1.42, P=0.52, I2=76%) were not significantly different. CONCLUSION: The use of AAT during EVT may improve functional outcomes and reduce mortality rates compared with ST alone, without an increased risk of sICH. These findings should be interpreted with caution pending the results from ongoing phase III trials to establish the efficacy and safety of AAT during EVT.