Analysis and therapeutic targeting of the IL-1R pathway in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings to both anaplastic lymphoma kinase positive (ALK+) and primary cutaneous (pC) ALK- ALCLs and identified an unexpected role of the interleukin-1R (IL-1R) inflammatory pathway in supporting the viability of pC ALK- ALCL. Importantly, this pathway is activated by IL-1α in an autocrine manner, which is essential for the induction and maintenance of protumorigenic inflammatory responses in pC-ALCL cell lines and primary cases. Hyperactivation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC-ALCL lines we analyze and is regulated by the nonproteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation and enhances the sensitivity of JAK inhibitors in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor, pacritinib, exhibited strong activities against pC ALK- ALCL, where the IL-1R pathway is hyperactivated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC-ALCL and provided opportunities for developing novel therapeutic strategies.

Tick-borne encephalitis virus capsid protein induces translational shutoff as revealed by its structural-biological analysis.

Tick-borne encephalitis virus (TBEV) is the most medically relevant tick-transmitted Flavivirus in Eurasia, targeting the host central nervous system and frequently causing severe encephalitis. The primary function of its capsid protein (TBEVC) is to recruit the viral RNA and form a nucleocapsid. Additional functionality of Flavivirus capsid proteins has been documented, but further investigation is needed for TBEVC. Here, we show the first capsid protein 3D structure of a member of the tick-borne flaviviruses group. The structure of monomeric Δ16-TBEVC was determined using high-resolution multidimensional NMR spectroscopy. Based on natural in vitro TBEVC homodimerization, the dimeric interfaces were identified by hydrogen deuterium exchange mass spectrometry (MS). Although the assembly of flaviviruses occurs in endoplasmic reticulum-derived vesicles, we observed that TBEVC protein also accumulated in the nuclei and nucleoli of infected cells. In addition, the predicted bipartite nuclear localization sequence in the TBEVC C-terminal part was confirmed experimentally, and we described the interface between TBEVC bipartite nuclear localization sequence and import adapter protein importin-alpha using X-ray crystallography. Furthermore, our coimmunoprecipitation coupled with MS identification revealed 214 interaction partners of TBEVC, including viral envelope and nonstructural NS5 proteins and a wide variety of host proteins involved mainly in rRNA processing and translation initiation. Metabolic labeling experiments further confirmed that TBEVC and other flaviviral capsid proteins are able to induce translational shutoff and decrease of 18S rRNA. These findings may substantially help to design a targeted therapy against TBEV.

Multimodal single-cell analysis of cutaneous T-cell lymphoma reveals distinct subclonal tissue-dependent signatures.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of mature T-cell neoplasms characterized by the accumulation of clonal malignant CD4+ T cells in the skin. The most common variant of CTCL, mycosis fungoides (MF ), is confined to the skin in early stages but can be accompanied by extracutaneous dissemination of malignant T cells to the blood and lymph nodes in advanced stages of disease. Sézary syndrome (SS), a leukemic form of disease, is characterized by significant blood involvement. Little is known about the transcriptional and genomic relationship between skin- and blood-residing malignant T cells in CTCL. To identify and interrogate malignant clones in matched skin and blood from patients with leukemic MF and SS, we combine T-cell receptor clonotyping with quantification of gene expression and cell surface markers at the single cell level. Our data reveal clonal evolution at a transcriptional and genetic level within the malignant populations of individual patients. We highlight highly consistent transcriptional signatures delineating skin- and blood-derived malignant T cells. Analysis of these 2 populations suggests that environmental cues, along with genetic aberrations, contribute to transcriptional profiles of malignant T cells. Our findings indicate that the skin microenvironment in CTCL promotes a transcriptional response supporting rapid malignant expansion, as opposed to the quiescent state observed in the blood, potentially influencing efficacy of therapies. These results provide insight into tissue-specific characteristics of cancerous cells and underscore the need to address the patients' individual malignant profiles at the time of therapy to eliminate all subclones.

Diagnosis of breast implant associated anaplastic large cell lymphoma by analysis of cytokines in peri-implant seromas.

More than 1300 women with breast implants have developed an anaplastic large cell lymphoma (ALCL) in fluid (seroma) around their implant. More often, seromas are due to benign causes, for example, capsule contracture, leakage, or trauma. Our report in American Journal of Hematology identified several cytokines (IL-9, IL-10, IL-13) as significantly elevated only in seromas due to ALCL. We further showed that the most robust biomarker, IL-10, could be detected by a lateral flow assay (similar to COVID detection) within minutes allowing physicians to quickly plan management, eliminate or reduce costly testing and patient time away from family. Early detection of ALCL in seromas before infiltration may avoid need for cytotoxic or immunotherapy and is possibly life-saving.

Evaluation of an established oncology triage hotline in a model of emergency department avoidance: assessing the UKONS triage tool and call outcomes.

PURPOSE: In response to a demonstrable need for 24/7, specialist oncology advice for patients undergoing systemic anti-cancer therapy, many healthcare institutions have adopted a telephone triage (TT) service. This is true of the Clatterbridge Cancer Centre which uses the UKONS framework to guide its decisions. This study aims to investigate the utilisation and outcomes of this TT service, with a focus on the most unwell call outcomes and factors leading to referrals to accident and emergency departments that could be mitigated with service development and modifications. METHODS: A retrospective evaluation study was conducted of calls occurring between 1st September 2021 and 31st August 2022. A descriptive analysis of call UKONS grading, triage outcome and primary complaint was performed. RESULTS: The TT hotline received 23,766 calls of which only 9066 were for clinical advice. Of the clinical calls, 45.2% were UKONS red. The majority of red calls 53.3% were directed to AED. The proportion of red calls going to AED changed drastically depending on the timing of call and the corresponding services available at those times, with 38.3% of reds being sent to AED in hours but 72.3% out of hours. The profile of complaints also showed significant differences in hours versus out of hours. CONCLUSION: Significant use of the hotline supports a genuine demand for oncology TT services. In order to reduce referrals to AED, this study supports the creation of alternative destinations of emergency care, especially out of hours.

Navigating language discordance in public health care in rural South Africa: a qualitative descriptive study of occupational therapists' perspectives.

BACKGROUND: Language discordance occurs in healthcare when staff and service users do not share proficiency in the same language. It is a global phenomenon impacting on the quality of health services, as person-centred practice requires communication to establish partnerships and rapport. In a country as linguistically diverse as South Africa, effective ways to navigate language discordance in health care are urgently required, yet there is limited research. This study aimed to describe how occupational therapists navigated language discordance when working in the public health sector in KwaZulu-Natal. METHODS: A qualitative descriptive design involved using purposive sampling to recruit occupational therapists as participants (n = 8) for 15 semi-structured interviews. Thematic analysis was used to analyse the data, which included reflective journal entries from all participants. RESULTS: The four emergent themes were: (1) concurrent use of strategies, (2) I'm doing as much I can, what more can I do? (3) Language definitely impacts that therapy process and lastly, (4) systemic oppression perpetuating language discordance. CONCLUSION: Language discordance is a complex context-specific phenomenon, therefore insight into concurrent use of strategies is important to practitioners to enable them to navigate language discordance and ensure provision of quality services. These insights are significant for healthcare professionals and resource allocators as they shed light on the shortcomings of advocating for a single strategy such as providing trained interpreters. Successful navigation is characterised by determination, being kind to oneself, willingness to learn and use of pragmatic and flexible approaches. To prepare to navigate language discordance in a low-resource context, education should extend in time and scope, to include multiple strategies, culture and relevant languages.

CD30 Regulation of IL-13-STAT6 Pathway in Breast Implant-Associated Anaplastic Large Cell Lymphoma.

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare, usually indolent CD30+ T-cell lymphoma with tumor cells, often surrounded by eosinophils, expressing IL-13 and pSTAT6. OBJECTIVES: The aim of this study was to understand the unique tumor pathology and growth regulation of BIA-ALCL, leading to potential targeted therapies. METHODS: We silenced CD30 and analyzed its effect on IL-13 signaling and tumor cell viability. IL-13 signaling receptors of BIA-ALCL cell lines were evaluated by flow cytometry and pSTAT6 detected by immunohistochemistry. CD30 was deleted by CRISPR/Cas9 editing. Effects of CD30 deletion on transcription of IL-13 and IL-4, and phosphorylation of STAT6 were determined by real-time polymerase chain reaction and western blotting. The effect of CD30 deletion on p38 mitogen-activated protein kinase (MAPK) phosphorylation was determined. Suppression of IL-13 transcription by a p38 MAPK inhibitor was tested. Tumor cell viability following CD30 deletion and treatment with a pSTAT6 inhibitor were measured in cytotoxicity assays. RESULTS: BIA-ALCL lines TLBR1 and TLBR2 displayed signaling receptors IL-4Rα, IL-13Rα1 and downstream pSTAT6. Deletion of CD30 by CRISPR/Cas9 editing significantly decreased transcription of IL-13, less so Th2 cytokine IL-4, and phosphorylation of STAT6. Mechanistically, we found CD30 expression is required for p38 MAPK phosphorylation and activation, and IL-13-STAT6 signaling was reduced by an inhibitor of p38 MAPK in BIA-ALCL tumor cells. Tumor cell viability was decreased by silencing of CD30, and a specific inhibitor of STAT6, indicating STAT6 inhibition is cytotoxic to BIA-ALCL tumor cells. CONCLUSIONS: These findings suggest reagents targeting the IL-13 pathway, pSTAT6 and p38 MAPK, may become useful for treating BIA-ALCL patients.

Safety and Efficacy of Bariatric Surgery in Cirrhosis Patients With Extreme Obesity.

OBJECTIVE: To assess the safety and efficacy of bariatric surgery in patients with cirrhosis. SUMMARY BACKGROUND DATA: Bariatric surgery may be a viable option for patients with cirrhosis and extreme obesity. However, the risk of liver decompensation after surgery is not thoroughly investigated. METHODS: We conducted a case-controlled study with 106 obese patients with cirrhosis (cases) and 317 age, sex, body mass index-, and type of surgery-matched obese patients without cirrhosis (controls) who underwent bariatric surgery. RESULTS: Patients with cirrhosis were predominantly Child-Pugh class A (97%) with the diagnosis established prior to surgery in only 46%. In the cirrhosis group, there was no death in the first 30 days compared with 1 patient in the control group. At 90 days there was 1 death in the cirrhosis group but no additional deaths in the control group. In total, 12 months after the surgery, there were 3 deaths in the cirrhosis group and 1 in the control group (2.8% vs 0.6%, P = 0.056). The surgery-related length of stay was significantly longer in patients with cirrhosis (3.7 ±â€Š4.0 vs 2.6 ±â€Š2.4 d, P = 0.001), but the 30-day readmission rate was lower (7.5% vs 11.9%, P = 0.001). The percent of total weight loss at 30 and 90-days was not significantly different between the groups and remained that way even at 1 year (29.1 ±â€Š10.9 vs 31.2 ±â€Š9.4%, P = 0.096). CONCLUSIONS: Bariatric surgery in obese cirrhotic patients is not associated with excessive mortality compared with noncirrhotic obese patients.

Paliperidone-Associated Sialorrhea: A Case Report With Review of Current Literature.

PURPOSE/BACKGROUND: Antipsychotic-associated sialorrhea is a problematic adverse effect with potentially negative consequences on quality of life and medication adherence. While clozapine is the antipsychotic that is most associated with sialorrhea, there have been published reports of other second-generation antipsychotics associated with sialorrhea, including aripiprazole, olanzapine, quetiapine, and risperidone. Although drooling is mentioned within the package insert for paliperidone, to date there have been minimal published reports in which paliperidone is implicated as the offending agent. METHODS/PROCEDURES: Here, we present a case of sialorrhea in a 56-year-old man with schizoaffective disorder who had a supratherapeutic paliperidone level after both oral and intramuscular paliperidone use. FINDINGS/RESULTS: Paliperidone was ultimately cross tapered to aripiprazole, and the patient was given atropine drops and benztropine with resolution of the sialorrhea. We provide a review of the literature regarding the other available reports of paliperidone-associated sialorrhea, possible mechanisms behind pathophysiology, as well as reports from the World Health Organization and Food and Drug Administration adverse event reporting systems. IMPLICATIONS/CONCLUSIONS: Clinicians should be aware of the potential for paliperidone and other nonclozapine second-generation antipsychotics to be associated with sialorrhea, especially given the increased frequency of their use for a variety of psychiatric disorders.

Do changes in primary care service use over time differ by neighbourhood income? Population-based longitudinal study in British Columbia, Canada.

BACKGROUND: Strong primary care systems have been associated with improved health equity. Primary care system reforms in Canada may have had equity implications, but these have not been evaluated. We sought to determine if changes in primary care service use between 1999/2000 and 2017/2018 differ by neighbourhood income in British Columbia. METHODS: We used linked administrative databases to track annual primary care visits, continuity of care, emergency department (ED) visits, specialist referrals, and prescriptions dispensed over time. We use generalized estimating equations to examine differences in the magnitude of change by neighbourhood income quintile, adjusting for age, sex/gender, and comorbidity, and stratified by urban/rural location of residence. We also compared the characteristics of physicians providing care to people living in low- and high-income neighbourhoods at two points in time. RESULTS: Between 1999/2000 and 2017/8 the average number of primary care visits per person, specialist referrals, and continuity of care fell in both urban and rural settings, while ED visits and prescriptions dispensed increased. Over this period in urban settings, primary care visits, continuity, and specialist referrals fell more rapidly in low vs. high income neighbourhoods (relative change in primary care visits: Incidence Rate Ratio (IRR) 0.881, 95% CI: 0.872, 0.890; continuity: partial regression coefficient -0.92, 95% CI: -1.18, -0.66; specialist referrals: IRR 0.711, 95%CI: 0.696, 0.726), while ED visits increased more rapidly (IRR 1.06, 95% CI: 1.03, 1.09). The percentage of physicians who provide the majority of visits to patients in neighbourhoods in the lower two income quintiles declined from 30.6% to 26.3%. CONCLUSION: Results raise concerns that equity in access to primary care has deteriorated in BC. Reforms to primary care that fail to attend to the multidimensional needs of low-income communities may entrench existing inequities. Policies that tailor patterns of funding and allocation of resources in accordance with population needs, and that align accountability measures with equity objectives are needed as part of further reform efforts.

Understanding factors that affect wellbeing in trans people "later" in transition: a qualitative study.

PURPOSE: Although cross-sectional studies have demonstrated that trans people present with lower quality of life and wellbeing than the general population, few studies have explored the factors associated with this, particularly in those who have medically transitioned some time ago. This paper aims to fill the gap in the literature on what factors are associated with wellbeing in trans people who initiated medical transition some time ago. METHODS: This study used semi-structured one-to-one interviews with 23 participants to investigate the factors that impact upon the wellbeing of trans people who had initiated Gender Affirming Medical Treatment five or more years ago. The content of the interviews were analysed with an inductive, grounded theory approach to identify common themes within them. RESULTS: The four themes identified include some consistencies with cisgender populations (while being viewed through the lens of trans experience), as well as those more specific to the trans experience. Together these themes were: Interactions with healthcare services; Seeking societal acceptance; Quality of social support; The 'double-edged sword' of media and social media. Each of the themes identifies a factor that participants highlighted as impacting, either positively or negatively, on their wellbeing. CONCLUSIONS: The results highlight the importance of social support, protective legislations, awareness of trans issues in the general public, and the need of improving the knowledge held by non-specialist healthcare providers.

Nonmalignant CD30+ Cells in Contralateral Peri-Implant Capsule of Patient With BIA-ALCL: A Premalignant Step?

CD30 lymphocyte activation antigen and phosphorylated STAT3 (pSTAT3) are consistent markers of tumor cells in breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). We present a case of BIA-ALCL in a breast implant capsule containing clustered tumor cells expressing CD30, pSTAT3, pSTAT6, interleukin 9, and granzyme B tumor cell biomarkers. Remarkably, the contralateral breast contained many scattered large, atypical CD30+ cells surrounded by inflammatory cells, raising a suspicion of bilateral BIA-ALCL, known to occur in some patients. To clarify the diagnosis, immunohistochemistry and multilabel immunofluorescence were performed. Unlike the tumor cells, the atypical CD30+ cells of the contralateral breast lacked pSTAT3, pSTAT6, interleukin 9, and granzyme B, eliminating a diagnosis of bilateral BIA-ALCL. This case highlights the importance of interpreting CD30 staining in the context of other tumor cell biomarkers and histopathology to avoid an incorrect diagnosis of BIA-ALCL. We believe the findings also suggest the possibility of CD30 expression as an early event in the multistep pathogenesis of BIA-ALCL.

IL-10, IL-13, Eotaxin and IL-10/IL-6 ratio distinguish breast implant-associated anaplastic large-cell lymphoma from all types of benign late seromas.

Breast implant-associated anaplastic large-cell lymphoma (BI-ALCL) is an uncommon peripheral T cell lymphoma usually presenting as a delayed peri-implant effusion. Chronic inflammation elicited by the implant has been implicated in its pathogenesis. Infection or implant rupture may also be responsible for late seromas. Cytomorphological examination coupled with CD30 immunostaining and eventual T-cell clonality assessment are essential for BI-ALCL diagnosis. However, some benign effusions may also contain an oligo/monoclonal expansion of CD30 + cells that can make the diagnosis challenging. Since cytokines are key mediators of inflammation, we applied a multiplexed immuno-based assay to BI-ALCL seromas and to different types of reactive seromas to look for a potential diagnostic BI-ALCL-associated cytokine profile. We found that BI-ALCL is characterized by a Th2-type cytokine milieu associated with significant high levels of IL-10, IL-13 and Eotaxin which discriminate BI-ALCL from all types of reactive seroma. Moreover, we found a cutoff of IL10/IL-6 ratio of 0.104 is associated with specificity of 100% and sensitivity of 83% in recognizing BI-ALCL effusions. This study identifies promising biomarkers for initial screening of late seromas that can facilitate early diagnosis of BI-ALCL.

Cell of Origin and Immunologic Events in the Pathogenesis of Breast Implant-Associated Anaplastic Large-Cell Lymphoma.

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a CD30-positive, anaplastic lymphoma kinase-negative T-cell lymphoma. Nearly all cases have been associated with textured implants. Most cases are of effusion-limited, indolent disease, with an excellent prognosis after implant and capsule removal. However, capsular invasion and tumor mass have a more aggressive course and a fatal outcome risk. This review summarizes the current knowledge on BIA-ALCL cell of origin and immunologic factors underlying its pathogenesis. Cytokine expression profiling of BIA-ALCL cell lines and clinical specimens reveals a predominantly type 17 helper T-cell (Th17)/Th1 signature, implicating this as its cell of origin. However, a Th2 allergic inflammatory response is suggested by the presence of IL-13, with infiltration of eosinophils and IgE-coated mast cells in clinical specimens of BIA-ALCL. The microenvironment-induced T-cell plasticity, a factor increasingly appreciated, may partially explain these divergent results. Mutations resulting in constitutive Janus kinase (JAK)-STAT activation have been detected and associated with BIA-ALCL pathogenesis in a small number of cases. One possible scenario is that an inflammatory microenvironment stimulates an immune response, followed by polyclonal expansion of Th17/Th1 cell subsets with release of inflammatory cytokines and chemokines and accumulation of seroma. JAK-STAT3 gain-of-function mutations within this pathway and others may subsequently lead to monoclonal T-cell proliferation and clinical BIA-ALCL. Current research suggests that therapies targeting JAK proteins warrant investigation in BIA-ALCL.

A novel model of controlling PD-L1 expression in ALK+ anaplastic large cell lymphoma revealed by CRISPR screening.

The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.

Recurrent MSC E116K mutations in ALK-negative anaplastic large cell lymphoma.

Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)+ or ALK-, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSC E116K, exclusively in ALK- ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSC E116K for ALK- ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin-bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculin-induced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation-sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30-IRF4-MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSC E116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs.

Granzyme B Is a Biomarker for Suspicion of Malignant Seromas Around Breast Implants.

BACKGROUND: Granzyme B (GrB) is a serine protease secreted, along with pore-forming perforin, by cytotoxic lymphocytes to mediate apoptosis in target cells. GrB has been detected in tumor cells associated with systemic and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) but its potential use for detection of early BIA-ALCL has not been fully investigated. OBJECTIVES: Prompted by the increased incidence of BIA-ALCL, the aim of this study was to assess GrB as a new biomarker to detect early disease in malignant seromas and to better understand the nature of the neoplastic cell. METHODS: A Human XL Cytokine Discovery Magnetic Luminex 45-plex Fixed Panel Performance Assay was used to compare cytokine levels in cell culture supernatants of BIA-ALCL and other T-cell lymphomas, as well as malignant and benign seromas surrounding breast implants. Immunohistochemistry was employed to localize GrB to cells in seromas and capsular infiltrates. RESULTS: Differences in GrB concentrations between malignant and benign seromas were significant (P < 0.001). GrB was found in and around apoptotic tumor cells, suggesting that the protease may be involved in tumor cell death. CONCLUSIONS: GrB is a useful marker for early detection of malignant seromas and to identify tumor cells in seromas and capsular infiltrates. Because there is an overlap between the lowest concentrations of soluble GrB in malignant seromas and the highest concentrations of GrB in benign seromas, it is recommended that GrB be used only as part of a panel of biomarkers for the screening and early detection of BIA-ALCL.

Evaluating the implementation of cervical cancer screening programs in low-resource settings globally: a systematized review.

PURPOSE: Cervical cancer disproportionately burdens low-resource populations where access to quality screening services is limited. A greater understanding of sustainable approaches to implement cervical cancer screening services is needed. METHODS: We conducted a systematized literature review of evaluations from cervical cancer screening programs implemented in resource-limited settings globally that included a formal evaluation and intention of program sustainment over time. We categorized the included studies using the continuum of implementation research framework which categorizes studies progressively from "implementation light" to more implementation intensive. RESULTS: Fifty-one of 13,330 initially identified papers were reviewed with most study sites in low-resource settings of middle-income countries (94.1%) ,while 9.8% were in low-income countries. Across all studies, visual inspection of the cervix with acetic acid (58.8%) was the most prevalent screening method followed by cytology testing (39.2%). Demand-side (client and community) considerations were reported in 86.3% of the articles, while 68.6% focused scientific inquiry on the supply side (health service). Eighteen articles (35.3%) were categorized as "Informing Scale-up" along the continuum of implementation research. CONCLUSIONS: The number of cervical cancer screening implementation reports is limited globally, especially in low-income countries. The 18 papers we classified as Informing Scale-up provide critical insights for developing programs relevant to implementation outcomes. We recommend that program managers report lessons learnt to build collective implementation knowledge for cervical cancer screening services, globally.

Association between concentrations of chromium in drinking water and mortality due to suicide in Alabama.

Preclinical studies and clinical data from case series and placebo-controlled trials suggest that chromium might have antidepressant effects. We conducted an observational study in order to assess the association between concentrations of chromium in drinking water and mortality due to suicide in Alabama. Publicly available databases were used to determine both county-level concentrations of chromium in drinking water and county-level rates of mortality due to suicide in the years 2005-2015. Data analyses comparing county-level concentrations of total chromium in drinking water with mortality rate due to suicide were conducted using a two-tailed nonparametric Spearman's rank correlation, with statistical significance set at p ≤ 0.01 and 99% confidence interval. Sub-analyses were conducted examining males, females, whites, and blacks/other minorities. There were no statistically significant findings concerning concentrations of chromium and suicide rate in the general population (p = 0.35, r = -0.12); however, there was a statistically significant inverse relationship between the concentration of chromium and suicide deaths in whites (p = 0.009, r = -0.32). There were no statistically significant findings in the remaining demographic subgroups. Chromium in drinking water might have a protective effect against mortality due to suicide, at least in the Caucasian population.

Cytokine receptor signaling is required for the survival of ALK- anaplastic large cell lymphoma, even in the presence of JAK1/STAT3 mutations.

Activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) mutations have been discovered in many T-cell malignancies, including anaplastic lymphoma kinase (ALK)- anaplastic large cell lymphomas (ALCLs). However, such mutations occur in a minority of patients. To investigate the clinical application of targeting JAK for ALK- ALCL, we treated ALK- cell lines of various histological origins with JAK inhibitors. Interestingly, most exogenous cytokine-independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with the STAT3 phosphorylation status of tumor cells. Using retroviral shRNA knockdown, we have demonstrated that these JAK inhibitor-sensitive cells are dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some, but not all, JAK inhibitor-sensitive cells. Moreover, the mutations alone cannot explain the JAK1/STAT3 dependency, given that wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in selected JAK inhibitor-sensitive cells. High expression levels of cytokines, including IL-6, were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest that cytokine receptor signaling is required for tumor cell survival in diverse forms of ALK- ALCL, even in the presence of JAK1/STAT3 mutations. Therefore, JAK inhibitor therapy might benefit patients with ALK- ALCL who are phosphorylated STAT3^.