Nuclear pore protein POM121 regulates subcellular localization and transcriptional activity of PPARγ.

Manipulation of the subcellular localization of transcription factors by preventing their shuttling via the nuclear pore complex (NPC) emerges as a novel therapeutic strategy against cancer. One transmembrane component of the NPC is POM121, encoded by a tandem gene locus POM121A/C on chromosome 7. Overexpression of POM121 is associated with metabolic diseases (e.g., diabetes) and unfavorable clinical outcome in patients with colorectal cancer (CRC). Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor with anti-diabetic and anti-tumoral efficacy. It is inhibited by export from the nucleus to the cytosol via the RAS-RAF-MEK1/2-ERK1/2 signaling pathway, a major oncogenic driver of CRC. We therefore hypothesized that POM121 participates in the transport of PPARγ across the NPC to regulate its transcriptional activity on genes involved in metabolic and tumor control. We found that POM121A/C mRNA was enriched and POM121 protein co-expressed with PPARγ in tissues from CRC patients conferring poor prognosis. Its interactome was predicted to include proteins responsible for tumor metabolism and immunity, and in-silico modeling provided insights into potential 3D structures of POM121. A peptide region downstream of the nuclear localization sequence (NLS) of POM121 was identified as a cytoplasmic interactor of PPARγ. POM121 positivity correlated with the cytoplasmic localization of PPARγ in patients with KRAS mutant CRC. In contrast, POM121A/C silencing by CRISPR/Cas9 sgRNA or siRNA enforced nuclear accumulation of PPARγ and activated PPARγ target genes promoting lipid metabolism and cell cycle arrest resulting in reduced proliferation of human CRC cells. Our data suggest the POM121-PPARγ axis as a potential drugable target in CRC.

Liver transplantation with interposition saphenous vein conduits for arterial reconstruction: Impact of morbidity and arterial ischemia time.

BACKGROUND: The outcomes of liver transplantation with hepatic arterial reconstruction using interposition saphenous vein conduits are not widely reported. Here, we share our experience using great saphenous vein conduits for hepatic arterial reconstruction in living donor liver transplantation. METHODS: This was a single-center retrospective review of patients who underwent living donor liver transplantation (n = 950). The saphenous vein conduits were used in 39 patients. We compared hepatic artery thrombosis, graft dysfunction, and 30-day and 1-year survival in the early (2012-2017) and late (2017-2020) transplant periods. RESULTS: Among 39 patients (of whom 30 [76.9%] were males, median Model for End-Stage Liver Disease was 24 [interquartile range, 17-27], median age was 50 [interquartile range, 43-54]), saphenous vein conduits were placed on supra celiac aorta in 7 (17.9%), infrarenal aorta in 25 (64.1%), and other arteries in 7 (17.9%) patients. The number of biliary and hepatic vein anastomoses, total arterial ischemia time, portal vein-hepatic artery reperfusion time, and duration of surgery was different in the 2 groups (P < .05). The 30-day mortality was 5/21 (23.8%) and 0 in the early and late periods (P = .05). The 30-day survival was >90% in patients with portal vein-hepatic artery reperfusion time <240 minutes, ≤2 grade 3 complications, no graft dysfunction, and later period of transplantation (P < .05). The 1-year survival with standard transplantation, transplantation with saphenous vein conduits in the early and late period was 87%, 62%, and 89% (P = .022). CONCLUSION: Liver transplantation with saphenous vein conduits is associated with acceptable outcomes. Major complications and arterial ischemia times are major determinants of outcomes.

BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer.

Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCIIloIL10+ macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24+CD44-CD40- B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1hiIL18hi tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy-responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease.

The use of algae for environmental sustainability: trends and future prospects.

Algae are photosynthetic prokaryotic or eukaryotic ubiquitously found group of organisms. Their enormous potentiality in coping up with various environmental crises has been well documented. Algae have proven to be ideal for biomonitoring of water pollution and help in removing the pollutants with their process of bioremediation apart from the production of eco-friendly sources of energy. Industries like food and pharmaceuticals are exploiting algae for producing several value-added products. The agricultural sector is also highly benefited from microalgae, as they are the good promoters of crop growth. The CO2-removing potential of algae proves to be an asset in fighting climate change. Moreover, the relatively easy and inexpensive methods of sampling and culturing of algae make them more popular. In this paper, we review the sustainable application aspects of algae in various areas like pollution control, energy production, agriculture, and fighting climate change. Critical discussions have been made on the recent trends and advances of algal technologies indicating future prospects.

Ticagrelor: A safe option as part of triple therapy?

Patients with atrial fibrillation who have concurrent coronary artery disease requiring percutaneous coronary intervention are subsequently prescribed dual antiplatelet therapy and anticoagulation resulting in triple therapy (TT). Ticagrelor, a reversibly binding P2Y12 antiplatelet agent, has shown superiority to clopidogrel in prevention of ischemic events and death, but is also associated with a small increase in the incidence of intracranial bleeding. This bleeding risk may be enhanced in the setting of TT. The objective of this report is to describe a case of a 70-year-old male prescribed TT with ticagrelor and to review the current literature on the safety of ticagrelor as a part of TT.

PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer.

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4+ T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-bet-IFN-γ- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+ T cells engaged PD-1+ macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.

γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming.

BACKGROUND AND AIMS: The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH). APPROACH AND RESULTS: We found that in SH, γδT cells are recruited to the liver by C-C chemokine receptor (CCR) 2, CCR5, and nucleotide-binding oligomerization domain-containing protein 2 signaling and are skewed toward an interleukin (IL)-17A+ phenotype in an inducible costimulator (ICOS)/ICOS ligand-dependent manner. γδT cells exhibit a distinct Vγ4+ , PD1+ , Ly6C+ CD44+ phenotype in SH. Moreover, γδT cells up-regulate both CD1d, which is necessary for lipid-based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL-17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet-induced SH and accelerates disease resolution. CONCLUSIONS: We demonstrate that hepatic γδT cells exacerbate SH, independent of IL-17 expression, by mitigating conventional CD4+ T-cell expansion and modulating their inflammatory program by CD1d-dependent vascular endothelial growth factor expression.

One Bone Forearm: A Valid Option For Treating Post Infection Bone Deficiencies.

Surgical fixation of radius to ulna has been described in the literature at various instances when deficiencies of either of the bones are encountered. The main concept of one bone forearm relies on an intact elbow and wrist articulations so a stable functioning limb can be achieved after union of radius to the ulna. This case report elaborates post infection loss of proximal ulna treated with fixation to radius.

Innate αß T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming.

Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαß+CD4-CD8-NK1.1- innate αß T cells (iαßT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαßTs represent ∼10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαßTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαßTs comprised ∼75% of the total intratumoral IL17+ cells. Moreover, iαßT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαßT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4+ and CD8+ T-cell expansion/activation and tumor protection. Collectively, iαßTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. SIGNIFICANCE: We found that iαßTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαßTs induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy.See related commentary by Banerjee et al., p. 1164.This article is highlighted in the In This Issue feature, p. 1143.

NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4+ T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8+ T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3-/- hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.

Unicompartmental Knee Arthroplasty: Indications, Outcomes, and Complications.

Unicompartmental knee arthroplasty (UKA) is a surgical option which is indicated in a special subset of osteoarthritis patients. Although it is often technically challenging, out-comes are positive when indications are followed as operative criteria. Benefits compared to total knee arthroplasty (TKA) include lower morbidity and a shorter recovery time. Potential complications include dislocation of the mobile-bearing surface, prosthesis loosening, and periprosthetic fracture. Revision surgery often involves a conversion to TKA, with outcomes comparable to revisions after TKA. 'he purpose of this review is to summarize the indications, outcomes, and complications of UKA, as well as the clinical outcomes after revision procedures.

Case Report of Ectopic Liver on Gallbladder Serosa with a Brief Review of the Literature.

This case describes an intraoperative incidental finding and surgical removal of ectopic liver tissue attached to the gallbladder during a standard laparoscopic cholecystectomy for acute cholecystitis. These anomalies are rare, with interesting associations and possible clinically relevant complications. The details of the case, along with a brief literature review of embryology, common ectopic sites, and associations/complications, are presented in this paper. Since laparoscopic cholecystectomy is a very common procedure, it is important to increase vigilance of ectopic liver tissues during surgeries to minimize complications and provide optimal management.

The epichaperome is an integrated chaperome network that facilitates tumour survival.

Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.

Association of transforming growth factor-ß1 gene C509T, G800A and T869C polymorphisms with intracerebral hemorrhage in North Indian Population: a case-control study.

Transforming growth factor-ß1 (TGF-ß1) is a multifunctional pro-inflammatory cytokine involved in inflammation and pathogenesis of cerebrovascular disease. As per our knowledge, there is no published study investigating the association between variations within the TGF-ß1 gene polymorphisms and risk of intracerebral hemorrhage (ICH). The aim of this study was to investigate the association of the TGF-ß1 gene (C509T, G800A and T869C) polymorphisms, and their haplotypes with the risk of ICH in North Indian population. 100 ICH patients and 100 age- and sex-matched controls were studied. Genotyping was performed using SNaPshot method. Conditional logistic regression analysis was used to calculate the strength of association between TGF-ß1 gene polymorphisms and risk of ICH. Hypertension, diabetes, dyslipidemia, low socioeconomic status, smoking, physical activity were found to be associated with the risk of ICH. The distribution of C509T, G800A and T869C genotypes was consistent with Hardy-Weinberg Equilibrium (HWE) in the ICH and control group. Adjusted conditional logistic regression analysis showed an independent association of TGF-ß1 G800A (OR 9.07; 95% CI 2.3-35.6; P = 0.002) and T869C (OR 5.1; 95 % CI 1.9-13.2; P = 0.001) with the risk of ICH under dominant model. Haplotype analysis showed that C509-G800-C869 and C509-A800-C869 haplotypes were significantly associated with the increased risk of ICH. C509T and T869C were in strong linkage disequilibrium (D' = 0.53, r(2) = 0.23). Our results suggest that TGF-ß1 (G800A, T869C) gene polymorphisms and their haplotypes are significantly associated with the risk of ICH in North Indian population. Further prospective studies with large sample size are required for independent validation. Our findings could be helpful in identifying individuals at increased risk for developing ICH.

Role of insertable cardiac monitors in anticoagulation therapy in patients with atrial fibrillation at high risk of bleeding.

AIMS: We aimed to ascertain whether an insertable cardiac monitor (ICM)-guided rhythm-control strategy and assessment of atrial fibrillation (AF) burden may allow safe withdrawal and obviate long-term use of oral anticoagulants (OACs) in AF patients at high bleeding risk. METHODS AND RESULTS: We implanted ICMs in 70 patients with AF with high risk of stroke (CHADS2 ≥2, CHA2DS2-VASc score ≥2) and bleeding (HAS-BLED score ≥3) after restoration of normal sinus rhythm (NSR) for continuous rhythm monitoring and optimization of antiarrhythmic drugs (AADs) when necessary. Patients were categorized into: (i) Group A (NSR/low AF burden, <1%), (ii) Group B (moderate/variable AF burden), and (iii) Group C (high AF burden, always AF). At patients' insistence, OACs were discontinued after proper counselling only if they maintained NSR/low AF burden for ≥3 consecutive months. All patients (age 73.3 ± 11.7 years; 53% male) were followed clinically and with ICM monitoring for 23.5 ± 10.5 months for outcomes including stroke, bleeding, death, device malfunction or infection, and AADs' adverse effects. Patients in Group A (n = 43), Group B (n = 20), and Group C (n = 7) had similar CHADS2 (2.09 ± 0.65, 2.05 ± 0.51, and 2.14 ± 0.38, respectively), CHA2DS2-VASc (3.05 ± 1.05, 2.85 ± 0.99, and 2.42 ± 0.53, respectively), and HAS-BLED (3.02 ± 1.01, 3.40 ± 0.68, and 3.00 ± 0.58, respectively) scores (P > 0.05). In 53 (76%) patients (Group A = 41 and Group B = 12) who maintained NSR/low AF burden, OACs were discontinued without adverse events. Severe bleeding occurred in 4 of 17 (24%) patients who remained on OACs. CONCLUSION: In AF patients with high bleeding risk, ICM-guided rhythm control with AADs and assessment of AF burden may allow safe discontinuation of OACs.

Response to Ponamgi et al. Comments on Khalighi et al. Takotsubo Cardiomyopathy: A Long Term Follow-up Shows Benefit with Risk Factor Reduction. J. Cardiovasc. Dev. Dis., 2015, 2, 273-281.

We appreciate the thorough response given by Ponagmi et al. [1], who rightly point out that the pathophysiology and modifiable risk factors of Takotsubo Cardiomyopathy (TC) have yet to be unequivocally established. [...].

Risk of Breast Cancer among Young Women and Importance of Early Screening.

BACKGROUND: Breast cancer is the most common type of cancer in women throughout the world. However, in comparison with Western women, it presents relatively early in women of Asian ethnicity. Early menarche, late menopause, use of OCP's, family history of benign or malignant breast disease, exposure to radiation and BMI in the under-weight range are well known risk factors for the development of breast cancer in premenopausal women. Early detection with the use of breast self-examination (BSE) and breast cancer screening programs can lead to a reduction in the mortality rates due to breast cancer. The aim of our study was to assess the risk factors for breast cancer among young women and to emphasize the importance of early screening among them. MATERIALS AND METHODS: We conducted a cross-sectional study among women aged 18 to 25 using a self- administered questionnaire. Data was collected over a period of 6 months from June to December, 2014. A total of 300 young women selected randomly from Dow Medical College and various departments of Karachi University successfully completed the survey. RESULTS: Respondents were 18-25 years of age (mean age=21.5). Out of the 300 young females, 90 (30%) had at least one risk factor, 90 (30%) had two, 40 (13%) had three, 8 (2.7%) had four, 2 (0.7%) had five while one female was found to have six positive risk factors for breast cancer. Some 66 women (22%) experienced symptoms of breast cancer such as non-cyclical pain and lumps. While 222 women (74%) had never performed breast self-examination, 22 (7.3%) had had a breast examination done by a health professional while 32 (10.7%) had participated in breast screening programs. A total of 223 (74.3%) women considered breast cancer screening important for young women. CONCLUSIONS: The percentage of young women with risk factors for breast cancer was found to be alarmingly high. Therefore, screening for breast cancer should start at an early age especially in high risk groups. Awareness about breast self-examination should be emphasized. Moreover, screening programs should be started to ensure early detection and reduction of mortality rates caused by breast cancer also in young Pakistani females.