Early effector maturation of naïve human CD8+ T cells requires mitochondrial biogenesis

The role of mitochondrial biogenesis during naïve to effector differentiation of CD8⁺ T cells remains ill explored. In this study, we describe a critical role for early mitochondrial biogenesis in supporting cytokine production of nascent activated human naïve CD8⁺ T cells. Specifically, we found that prior to the first round of cell division activated naïve CD8⁺ T cells rapidly increase mitochondrial mass, mitochondrial respiration, and mitochondrial reactive oxygen species (mROS) generation, which were all inter‐linked and important for CD8⁺ T cell effector maturation. Inhibition of early mitochondrial biogenesis diminished mROS dependent IL‐2 production – as well as subsequent IL‐2 dependent TNF, IFN‐γ, perforin, and granzyme B production. Together, these findings point to the importance of mitochondrial biogenesis during early effector maturation of CD8⁺ T cells.     

Human regulatory T cells lack the cyclophosphamide‐extruding transporter ABCB1 and are more susceptible to cyclophosphamide‐induced apoptosis

ATP‐binding cassette (ABC) transporters, including ABC‐transporter B1 (ABCB1), extrude drugs, metabolites, and other compounds (such as mitotracker green (MTG)) from cells. Susceptibility of CD4⁺ regulatory T (Treg) cells to the ABCB1‐substrate cyclophosphamide (CPA) has been reported. Here, we characterized ABCB1 expression and function in human CD4⁺ T‐cell subsets. Naïve, central memory, and effector‐memory CD4⁺ T cells, but not Treg cells, effluxed MTG in an ABCB1‐dependent manner. In line with this, ABCB1 mRNA and protein was expressed by nonregulatory CD4⁺ T‐cell subsets, but not Treg cells. In vitro, the ABCB1‐substrate CPA was cytotoxic for Treg cells at a 100‐fold lower dose than for nonregulatory counterparts, and, inversely, verapamil, an inhibitor of ABC transporters, increased CPA‐toxicity in nonregulatory CD4⁺ T cells but not Treg cells. Thus, Treg cells lack expression of ABCB1, rendering them selectively susceptible to CPA. Our findings provide mechanistic support for therapeutic strategies using CPA to boost anti‐tumor immunity by selectively depleting Treg cells.     

Genetic variant association of PTPN22, CTLA4, IL2RA,as well as HLA frequencies in susceptibility to alopecia areata

ABSTRACT

Alopecia areata (AA) is characterized by a genetically complex inheritance. HLA frequencies, as well as the single nucleotide polymorphism (SNP) in PTPN22, CTLA4, and IL2RA genes, have been described to be associated with AA susceptibility. So far, no independent replication of these studies has been reported, and no data exist on a possible association between AA disease and these SNPs or influence of HLA frequencies in Iranian population. A possible association between HLA-DRB1*11 alleles as well as a single variation in PTPN22, CTLA4, and IL2RA genes and patchy AA disease have been investigated in a cohort from Iran. Patient and control subjects were genotyped for PTPN22 (rs2476601), CTLA4 (rs3087243), and IL2RA (rs3118470) variations as well as HLA frequencies. Gene expression levels were analyzed by real-time RT-PCR. In contrast to PTPN22 and CTLA4 gene polymorphisms, a significant association was found between IL2RA SNP and susceptibility to AA in Iranian cohort. While gene expression levels of IL2RA and PTPN22 were higher in the patients than that of controls, CTLA4 expression levels found significantly lower in the patients. Despite a significant association between AA and HLA-DRB1*11 frequencies, the presence of DRB1*11 is not associated with PTPN22, CTLA4, or IL2RA gene SNPs. Although the minor allele in IL2RA SNP can be a significant determinant of AA disease development in Iranian population, reported an association between the PTPN22 and CTLA4 variations was not confirmed by our study. Furthermore, these genetic risk factors might act independently from HLA alleles.     

Cellular diversity of human placental stem villi: an ultrastructural and immunohistochemical study

The aim of the study was to investigate the distribution and differentiation of cell types in the stroma of human placental stem villi (SV). A total of 14 human term placental tissues were studied. Double immunolabeling was performed for desmin-vimentin, desmin--smooth actin and vimentin--smooth actin. Cytokeratin 7, proliferating cell nuclear antigen immunolabeling was also performed. Parallel tissue samples were examined by transmission electron microscopy. HSCORE was performed for the semi-quantitative analysis of distribution of cells in the stroma of SV. Vimentin-labeled cells were mostly distributed in the subtrophoblastic area. Desmin-vimentin double immunolabeling was mainly localized in the triangular area and to a lesser degree in the perivascular area and vessel walls (p=<0.001). However, desmin- smooth actin labeling was observed predominantly in the vessel wall and perivascular area. Vimentin- smooth actin immunoreactivity was significantly stronger in the triangular and perivascular areas compared to the vessel walls (p=0.003).

Ultrastructurally, cells in the stroma of SV were mesenchyme cells, reticulum cells, fibroblasts, myofibroblasts, smooth muscle cells, and Hofbauer cells, filamented and vacuolated cells. The differentiation of myofibroblasts in the triangular and perivascular areas may play a role in maturation of SV and villous contractility, modulation of the intervillous space and this may have effects on maternofetal placental circulation.     

Osteomyelitis as a late complication of Bacille Calmette-Guérin vaccination.

Bacille Calmette-Guérin (BCG) osteomyelitis is a very rare complication of BCG vaccination. We report a 14-month-old boy who received BCG vaccination at birth. He developed pain and swelling in his left calf at 11 months of age. BCG osteomyelitis was diagnosed in right femur and left tibia. He had no evidence of immunodeficiency. After antituberculous therapy and surgical treatment, the bone lesions disappeared and he was discharged from hospital without any sequela during 11 months of follow-up.     

Targeted intraoperative radiotherapy tumour bed boost during breast-conserving surgery after neoadjuvant chemotherapy

Introduction

The use of targeted intraoperative radiotherapy (TARGIT-IORT) as a tumour bed boost during breast-conserving surgery (BCS) for breast cancer has been reported since 1998. We present its use in patients undergoing breast conservation following neoadjuvant therapy (NACT).

Method

In this retrospective study involving 116 patients after NACT we compared outcomes of 61 patients who received a tumour bed boost with IORT during lumpectomy versus 55 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Local recurrence-free survival (LRFS), disease-free survival (DFS), distant disease-free survival (DDFS), breast cancer mortality (BCM), non-breast cancer mortality (NBCM) and overall mortality (OS) were compared.

Results

Median follow up was 49 months. The differences in LRFS, DFS and BCM were not statistically significant. The 5?year Kaplan–Meier estimate of OS was significantly better by 15% with IORT: IORT 2 events (96.7%, 95%CI 87.5–99.2), EBRT 9 events (81.7%, 95%CI 67.6–90.1), hazard ratio (HR) 0.19 (0.04–0.87), log rank p = 0.016, mainly due to a reduction of 10.1% in NBCM: IORT 100%, EBRT 89.9% (77.3–95.7), HR (not calculable), log rank p = 0.015. The DDFS was as follows: IORT 3 events (95.1%, 85.5–98.4), EBRT 12 events (69.0%, 49.1–82.4), HR 0.23 (0.06–0.80), log rank p = 0.012.

Conclusion

IORT during lumpectomy after neoadjuvant chemotherapy as a tumour bed boost appears to give results that are not worse than external beam radiotherapy boost. These data give further support to the inclusion of such patients in the TARGIT-B (boost) randomised trial that is testing whether IORT boost is superior to EBRT boost.

     

The effect of the modes of delivery on the maternal and neonatal dynamic thiol–disulfide homeostasis

Abstract

Background: Thiols are organic compounds containing sulfhydryl groups which exert antioxidant effects via dynamic thiol–disulfide homeostasis. The shift towards disulfide indicates the presence of oxidative environment. The thiol–disulfide homeostasis has not been studied in different mode of delivery before.

Aims: To investigate the effects of mode of parturition on the thiol–disulfide homeostasis in mothers and term infants.

Study design: The participants were grouped according to the mode of their delivery: group vaginal delivery (VD, n?=?40) and group cesarean section (C/S, n?=?40). Three serum samples were collected: from mothers at the beginning of labor, from the cord blood (CB), and from the infants at the 24th hour after birth. The dynamic thiol–disulfide homeostasis in both groups were compared.

Results: The levels of native-thiol and total-thiol in CB were significantly higher in VD group than those with C/S group. The levels of disulfide were higher in infants born by C/S compared with those born by VD. The disulfide-to-native thiol ratio, disulfide-to-total thiol ratio, and native thiol-to-total thiol ratio were similar between two groups.

Conclusion: Our results showed that the dynamic thiol–disulfide homeostasis of the neonate was greatly influenced by the way of delivery and supported that vaginally delivered infants have less oxidative stress.     

Endometriomas in Adolescents and Young Women

Study ObjectiveTo evaluate clinical aspects of endometriomas encountered in late adolescent females and young women and to review the issues specifically related to the disease in this age group.DesignRetrospective medical chart review study.SettingAdolescent gynecology and infertility clinic of a tertiary care hospital with women's health focus.ParticipantsSixty-three late adolescent females and young women aged ≤24 years with endometrioma.InterventionsOperative laparoscopy for endometriomas.Main Outcome MeasuresBaseline clinical characteristics of the patients including age, marital status, body mass index, symptoms on admission, family history of endometriosis, past medical history, CA-125 levels, presence of a müllerian anomaly, endometriosis characteristics at the time of surgery, and correlation between ASRM scores and patient characteristics.ResultsThe mean age and body mass index of the patients were 22 ± 2 (range 17-24) years and 20.8 ± 2.6 (range 16.6-28.5) kg/m² respectively. Chronic pelvic pain was the most common symptom (44%). Two patients had a diagnosis of genital malformation. Forty-one (65%) patients had endometrioma on the right ovary, and 14 (22%) patients had bilateral endometriomas. Only one patient had posterior cul-de-sac completely obliterated. Fifty-five (87%) patients had score <16 points for adnexal adhesions calculated according to the revised American Society for Reproductive Medicine classification.ConclusionEndometriomas, although rare, can be encountered in adolescents and young women. The disease in adolescent patient group offers particular importance since early intervention is essential in order to decrease pain, prevent progression of the disease and enhance future fertility.     

Leveraging social capital: multilevel stigma,associated HIV vulnerabilities,and social resilience strategies among transgender women in Lima,Peru

Introduction : In Peru, transgender women (TW) experience unique vulnerabilities for HIV infection due to factors that limit access to, and quality of, HIV prevention, treatment and care services. Yet, despite recent advances in understanding factors associated with HIV vulnerability among TW globally, limited scholarship has examined how Peruvian TW cope with this reality and how existing community‐level resilience strategies are enacted despite pervasive social and economic exclusion facing the community. Addressing this need, our study applies the understanding of social capital as a social determinant of health and examines its relationship to HIV vulnerabilities to TW in Peru. Methods : Using qualitative methodology to provide an in‐depth portrait, we assessed (1) intersections between social marginalization, social capital and HIV vulnerabilities; and (2) community‐level resilience strategies employed by TW to buffer against social marginalization and to link to needed HIV‐related services in Peru. Between January and February 2015, 48 TW participated (mean age = 29, range = 18–44) in this study that included focus group discussions and demographic surveys. Analyses were guided by an immersion crystallization approach and all coding was conducted using Dedoose Version 6.1.18. Results : Themes associated with HIV vulnerability included experiences of multilevel stigma and limited occupational opportunities that placed TW at risk for, and limited their engagement with, existing HIV services. Emergent resiliency‐based strategies included peer‐to‐peer and intergenerational knowledge sharing, supportive clinical services (e.g. group‐based clinic attendance) and emotional support through social cohesion (i.e. feeling part of a community). Conclusion : This study highlights the importance of TW communities as support structures that create and deploy social resiliency‐based strategies aimed at deterring and mitigating the impact of social vulnerabilities to discrimination, marginalization and HIV risk for individual TW in Peru. Public health strategies seeking to provide HIV prevention, treatment and care for this population will benefit from recognizing existing social capital within TW communities and incorporating its strengths within HIV prevention interventions. At the intersection of HIV vulnerabilities and collective agency, dimensions of bridging and bonding social capital emerged as resiliency strategies used by TW to access needed healthcare services in Peru. Fostering TW solidarity and peer support are key components to ensure acceptability and sustainability of HIV prevention and promotion efforts.