Miracle-dz/UniFAR-FTUs huggingface dataset:
MALIGNANT MELANOMA: SOME ASPECTS OF PATHOLOGY AND PROGNOSIS

Abstract This is a report on the periods of survival, and the factors that influence survival, in a series of 509 patients treated for malignant melanoma in the Peter MacCallum clinic, Melbourne. Not the least of these factors is education of the public and the medical profession in its early recognition, which has greatly improved the prognosis. In this context, it is also firmly believed that whenever possible, one clinician only should be responsible for the total surgical management of any suffering from this disease.
Preterm neonates display altered plasmacytoid dendritic cell function and morphology

Bacterial and viral infections cause high rates of morbidity and mortality in premature newborns. In the setting of viral infection, pDCs play a key role as strong producers of IFN‐α upon TLR9 activation. We analyzed pDC frequency, phenotype, morphology, and function in CB of preterm and term newborns in comparison with adults. Whereas all age groups show similar pDC numbers, BDCA‐2, CD123, and TLR9 levels, the expression of BDCA‐4 and capacity to produce IFN‐α upon TLR9 challenge were decreased significantly in preterm neonates. Furthermore, we show by means of electron microscopy that pDCs from preterm newborns exhibit a distinct, “immature” morphology. Taken together, these findings suggest decreased functionality of pDCs in the premature newborn. The reduced capacity to produce IFN‐α is likely to render such infants more susceptible to viral infections.
The intracellular progesterone receptor regulates CD4+ T cells and T cell‐dependent antibody responses

Pg has distinct immunomodulatory properties involved in poorly understood immune phenomena, including maternal tolerance of the fetus, increased risk of certain infections during pregnancy or after Pg birth control, and pregnancy‐associated remission of autoimmune disease. Several potential mechanisms have been identified, including alteration of Th1 and Treg activity, but the precise cellular and molecular targets of Pg immunomodulation in vivo remain obscure, partly because Pg can signal through several different receptor types. One such receptor, the iPR, encoded by the pgr gene, is essential for reproduction in female mice and is expressed in the thymus and CD4+ T cells. We hypothesized that iPR regulates CD4+ T cell activity and adaptive immune responses in vivo. With the use of iPR KO mice, we demonstrate that iPR specifically suppresses TD antibody responses, primarily by dampening CD4+ Teff activity, likely via transcriptional repression of the IFN‐γ gene and modulation of other programs regulating CD4+ T cells. Our results highlight a novel mechanism linking the endocrine and immune systems, and they offer insight into important but poorly understood phenomena in womenˈs health and autoimmunity.
A 915MHz 120μW-RX/900μW-TX envelope-detection transceiver with 20dB in-band interference tolerance

Minimizing the power consumption while maintaining performance is paramount in radio transceiver design for low-power wireless sensor network (WSN) applications. Given a sub-mW power budget, many radios have utilized amplitude modulation and envelope detection to eliminate the need for accurate frequency references and to reduce power consumption [1-4]. However, such radios suffer from poor frequency selectivity. They rely on front-end filters to reject out-of-band interference, while in-band interferers still corrupt the desired signal.
Impact of Subnormothermic Machine Perfusion Preservation in Severely Steatotic Rat Livers: A Detailed Assessment in an Isolated Setting

The current drastic shortage of donor organs has led to acceptance of extended‐criteria donors for transplantation, despite higher risk of primary nonfunction. Here, we report the impact of subnormothermic machine perfusion (SMP) preservation on the protection of >50% macrosteatotic livers. Dietary hepatic steatosis was induced in Wistar rats via 2‐day fasting and subsequent 3‐day re‐feeding with a fat‐free, carbohydrate‐rich diet. This protocol induces 50–60% macrovesicular steatosis, which should be discarded when preserved via cold storage (CS). The fatty livers were retrieved and preserved for 4 h using either CS in histidine‐tryptophan‐ketoglutarate or SMP in polysol solution. Graft functional integrity was evaluated via oxygenated ex vivo reperfusion for 2 h at 37°C. SMP resulted in significant reductions in not only parenchymal alanine aminotransferase (p < 0.001), but also mitochondrial glutamate dehydrogenase (p < 0.001) enzyme release. Moreover, portal venous pressure (p = 0.047), tissue adenosine triphosphate (p = 0.001), bile production (p < 0.001), high‐mobility group box protein‐1 (p < 0.001), lipid peroxidation, and tissue glutathione were all significantly improved by SMP. Electron microscopy revealed that SMP alleviated deleterious alterations of sinusoidal microvasculature and hepatocellular mitochondria, both of which are characteristic disadvantages associated with steatosis. SMP could protect 50–60% macrosteatotic livers from preservation/reperfusion injury, and may thus represent a new means for expanding available donor pools.
OPTN/SRTR 2015 Annual Data Report: Pancreas

The number of pancreas transplants performed in the United States stabilized over the last 3 years after nearly a decade of steady decline. Numbers of new additions to the list also stabilized during the same period. Notably, the persistent decline in pancreas after kidney transplants also seems to have abated, at least for now. The first full year of data after implementation of the new pancreas allocation system revealed no change in the distribution of organs between simultaneous pancreas‐kidney (SPK) transplant and pancreas transplant alone. The percentage of kidneys used in SPK transplants was also unchanged. While a uniform definition of pancreas graft failure was approved in June 2015, it is awaiting implementation. Meanwhile, SRTR will refrain from publishing pancreas graft failure data in the program‐specific reports. Therefore, it is difficult to track trends in outcomes after pancreas transplant over the past 2 years. New initiatives by the OPTN/UNOS Pancreas Transplantation Committee include facilitated pancreas allocation and broadened allocation of pancreata across compatible ABO blood types to increase organ utilization.
Association of Higher CD4+CD25highCD127low, FoxP3+, and IL‐2+ T Cell Frequencies Early After Lung Transplantation With Less Chronic Lung Allograft Dysfunction at Two Years

Regulatory T cells (Treg) can regulate alloantigens and may counteract chronic lung allograft dysfunction (CLAD) in lung transplantation. We analyzed Treg in peripheral blood prospectively and correlated percentages of subpopulations with the incidence of CLAD at 2 years. Among lung‐transplanted patients between January 2009 and July 2011, only patients with sufficient Treg measurements were included into the study. Tregs were measured immediately before lung transplantation, at 3 weeks and 3, 6, 12, and 24 months after transplantation and were defined as CD4+CD25high T cells and further analyzed for CTLA4, CD127, FoxP3, and IL‐2 expressions. Between January 2009 and July 2011, 264 patients were transplanted at our institution. Among the 138 (52%) patients included into the study, 31 (22%) developed CLAD within 2 years after transplantation. As soon as 3 weeks after lung transplantation, a statistically significant positive association was detected between Treg frequencies and later absence of CLAD. At the multivariate analysis, increasing frequencies of CD4+CD25highCD127low, CD4+CD25highFoxP3+ and CD4+CD25highIL‐2+ T cells at 3 weeks after lung transplantation emerged as protective factors against development of CLAD at 2 years. In conclusion, higher frequencies of specific Treg subpopulations early after lung transplantation are protective against CLAD development.
A 32Gb/s wireline receiver with a low-frequency equalizer, CTLE and 2-tap DFE in 28nm CMOS

Standards such as OIF CEI-25G, CEI-28G and 32G-FC require transceivers operating at high data rates over imperfect channels. Equalizers are used to cancel the inter-symbol interference (ISI) caused by frequency-dependent channel losses such as skin effect and dielectric loss. The primary objective of an equalizer is to compensate for high-frequency loss, which often exceeds 30dB at fs/2. However, due to the skin effect in a PCB stripline, which starts at 10MHz or lower, we also need to compensate for a small amount of loss at low frequency (e.g., 500MHz). Figure 2.1. 1 shows simulated responses of a backplane channel (42.6dB loss at fs/2 for 32Gb/s) with conventional high-frequency equalizers only (4-tap feed-forward equalizer (FFE), 1st-order continuous-time linear equalizer (CTLE) with a dominant pole at fs/4, and 1-tap DFE) and with additional low-frequency equalization. Conventional equalizers cannot compensate for the small amount of low-frequency loss because the slope of the low-frequency loss is too gentle (<;3dB/dec). The FFE and CTLE do not have a pole in the low frequency region and hence have only a steep slope of 20dB/dec above their zero. The DFE cancels only short-term ISI. Effects of such low-frequency loss have often been overlooked or neglected, because 1) the loss is small (2 to 3dB), 2) when plotted using the linear frequency axis which is commonly used to show frequency dependence of skin effect and dielectric loss, the low-frequency loss is degenerated at DC and hardly visible (Fig. 2.1.1a), and 3) the long ISI tail of the channel pulse response seems well cancelled at first glance by conventional equalizers only (Fig. 2.1.1b). However, the uncompensated low-frequency loss causes non-negligible long-term residual ISI, because the integral of the residual ISI magnitude keeps going up for several hundred UI. As shown by the eye diagrams in the inset of Fig. 2.1. 1(b), the residual long-term ISI results in 0.42UI data-dependent Jitter (DDJ) that is difficult to reduce further by enhancing FFE/CTLE/DFE, but can be reduced to 0.21UI by adding a low-frequency equalizer (LFEQ). Savoj et al. also recently reported long-tail cancellation [2].
Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy

Background Early infantile epileptic encephalopathies usually manifest as severely impaired cognitive and motor development and often result in a devastating permanent global developmental delay and intellectual disability. A large set of genes has been implicated in the aetiology of this heterogeneous group of disorders. Among these, the ion channelopathies play a prominent role. In this study, we investigated the genetic cause of infantile epilepsy in three affected siblings. Methods and results Homozygosity mapping in DNA samples followed by exome analysis in one of the patients resulted in the identification of a homozygous mutation, p.L1040P, in the CACNA2D2 gene. This gene encodes the auxiliary α2δ2 subunit of high voltage gated calcium channels. The expression of the α2δ2-L1040P mutant instead of α2δ2 wild-type (WT) in Xenopus laevis oocytes was associated with a notable reduction of current density of both N (CaV2.2) and L (CaV1.2) type calcium channels. Western blot and confocal imaging analyses showed that the α2δ2-L1040P mutant was synthesised normally in oocyte but only the α2δ2-WT, and not the α2δ2-L1040P mutant, increased the expression of α1B, the pore forming subunit of CaV2.2, at the plasma membrane. The expression of α2δ2-WT with CaV2.2 increased the surface expression of α1B 2.5–3 fold and accelerated current inactivation, whereas α2δ2-L1040P did not produce any of these effects. Conclusions L1040P mutation in the CACNA2D2 gene is associated with dysfunction of α2δ2, resulting in reduced current density and slow inactivation in neuronal calcium channels. The prolonged calcium entry during depolarisation and changes in surface density of calcium channels caused by deficient α2δ2 could underlie the epileptic phenotype. This is the first report of an encephalopathy caused by mutation in the auxiliary α2δ subunit of high voltage gated calcium channels in humans, illustrating the importance of this subunit in normal physiology of the human brain.
The Effects of the Norsk Funktion-Walking Orthosis on the Walking Ability of Children With Cerebral Palsy and Severe Gait Impairment

The purpose of this study was 1) to test whether an orthosis, which provides postural stability of the trunk and guides the leg movements during walking (Norsk Funktion-walker orthosis [NFWO]), would enable nonambulant children with cerebral palsy with poor or no leg coordination and with little or no trunk control to walk on their own, 2) to investigate if there is an increase in motor function and activity while using a NFWO, and 3) defining requirements for a successful provision. Ninety-three children (39 girls, 54 boys; mean age 7.6 years; 67 with bilateral spastic, 10 with dyskinetic, 10 with mixed, 6 with ataxic cerebral palsy; Gross Motor Function classification System level 4: 45, level 5: 48) were provided with a NFWO. The following assessments were carried out immediately before and 3 months after using the NFWO: WeeFIM walking score; independence rating by parents or caregivers; aims or expectations of parents or caregivers; at a mean interval of 265 days after provision: mean daily walking distance (meters). With the NFWO, 78 children (84%) became ambulatory, 10 children (11%) used it exclusively as a dynamic standing frame only, and 5 children (5%) returned the NFWO. The mean daily walking distance was 99 m (2–463 m). The mean WeeFIM walking score of 1.99 (SD 0.83) without the NFWO increased to 4.42 (SD 1.00) with the NFWO indoors and to 3.71 (SD 1.24) (p < 0.001) outdoors. Independence rating by parents or caregivers reflected a highly significant increase in independent mobility with the NFWO compared with locomotion without ambulatory aides (p < 0.001) and of bilateral hand function (p < 0.001). No significant increase in the mobility was found when comparing former mobility aides (wheelchair, tricycle) with the NFWO. The ability to cross obstacles did neither significantly increase with the NFWO. Successful indication for a NFWO depends on 1) the child’s motivation to walk and the support of the environment to achieve independent walking mobility through the use of this assistive tool, 2) the ability for selective reciprocal leg movements, and 3) no flexion contractures of hips and knees above 20° and a foot dorsiflexion of at least neutral-0°. The NFWO proved to be a useful ambulatory aid in the children with cerebral palsy with severe gait impairment to increase independent mobility.
Integrating APOL1 Gene Variants Into Renal Transplantation: Considerations Arising From the American Society of Transplantation Expert Conference

Thirteen percent of individuals of African ancestry express two variant copies of the gene encoding apolipoprotein 1 (APOL1) that has been associated with an increased risk of end‐stage renal disease (ESRD) in the general population. Limited studies suggest that the survival of transplanted kidneys from donors expressing two APOL1 risk alleles is inferior to that of kidneys from donors with zero or one risk allele. In living kidney donation, two case reports describe donors expressing two APOL1 risk alleles who developed ESRD. Given the potential impact of APOL1 variants on the utility and safety of kidney transplantation and living kidney donation, the American Society of Transplantation convened a meeting with the goals of summarizing the current state of knowledge with respect to transplantation and APOL1, identifying knowledge gaps and studies to address these gaps, and considering approaches to integrating APOL1 into clinical practice. The authors recognize that current data are not sufficient to support traditional evidence‐based guidelines but also recognize that it may require several years to generate the necessary data. Thus, approaches as to how APOL1 might currently be integrated into the clinical decision‐making process were considered. This report summarizes the group's deliberations.
A 130.7mm2 2-layer 32Gb ReRAM memory device in 24nm technology

ReRAM has been considered as one of the potential technologies for the next-generation nonvolatile memory, given its fast access speed, high reliability, and multi-level capability. Multiple-layered architectures have been used for several megabit test-chips and memory macros [1-3]. This paper presents a MeOx-based 32Gb ReRAM test chip developed in 24nm technology.
Mucosal immunopathogenesis of HIV infection: implications for vaccine development

Recent discoveries in the immunology and pathogenesis of HIV infection have fundamentally changed our understanding of primary HIV infection, and have the potential to revolutionize future HIV vaccine and therapeutic strategies. What was once thought of as a slow or even ‘latent’ viral infection, is now known to be an infection that rapidly infects and destroys the majority of memory CD4+CCR5+ T cells within days, or at least weeks, of primary infection, particularly those residing in mucosal effector sites. Unfortunately, these cells may be critical for generating or maintaining effective immune responses for both humoral and cell-mediated arms of the immune system, which could explain why the vast majority of HIV-infected patients develop AIDS, and our continuing difficulty in developing an effective vaccine. Recent advances in our understanding of acute HIV infection, the importance of the mucosal immune system in HIV pathogenesis, and the implications of these aspects in relation to vaccine approaches.
Associations of common variants in HFE and TMPRSS6 with iron parameters are independent of serum hepcidin in a general population: a replication study

Background Genome-wide association studies have convincingly shown that single nucleotide polymorphisms (SNPs) in HFE and TMPRSS6 are associated with iron parameters. It was commonly thought that these associations could be explained by the intermediate effect on hepcidin concentration. A recent study in an isolated Italian population, however, concluded that these associations were not exclusively dependent on hepcidin values. We report here the second study to investigate the role of hepcidin in the associations between common variants in HFE and TMPRSS6 with iron parameters. Methods We extracted 101 SNPs in HFE and TMPRSS6 from genome-wide imputed SNP data of 1832 individuals from the general population (Nijmegen Biomedical Study). Single locus and haplotype associations with serum iron parameters and hepcidin were studied using linear regression analyses. Results We found that HFE rs1800562 and TMPRSS6 rs855791 are the main determinants of HFE and TMPRSS6 related variation in serum iron, ferritin, transferrin saturation, and total iron binding capacity. These SNPs are associated with the ratios hepcidin/ferritin (p<1×10−5) and hepcidin/transferrin saturation (p<1×10−3), but not with serum hepcidin (p>0.2). Adjustment for hepcidin or the ratio hepcidin/ferritin did not decrease the strength of the SNP–iron parameter associations. Conclusions Our results do not support an intermediate role for hepcidin in the SNP–iron parameter associations, which confirms previous findings, and indicate a pleiotropic SNP effect on the hepcidin ratios and the iron parameters. Taken together, this suggests that there might be other, yet unknown, serum hepcidin independent mechanisms which play a role in the association of HFE and TMPRSS6 variants with serum iron parameters.
Cytomegalovirus‐Responsive CD8+ T Cells Expand After Solid Organ Transplantation in the Absence of CMV Disease

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in solid organ transplant recipients. Approximately 60% of adults are CMV seropositive, indicating previous exposure. Following resolution of the primary infection, CMV remains in a latent state. Reactivation is controlled by memory T cells in healthy individuals; transplant recipients have reduced memory T cell function due to chronic immunosuppressive therapies. In this study, CD8+ T cell responses to CMV polypeptides immediate‐early‐1 and pp65 were analyzed in 16 CMV‐seropositive kidney and heart transplant recipients longitudinally pretransplantation and posttransplantation. All patients received standard of care maintenance immunosuppression, antiviral prophylaxis, and CMV viral load monitoring, with approximately half receiving T cell–depleting induction therapy. The frequency of CMV‐responsive CD8+ T cells, defined by the production of effector molecules in response to CMV peptides, increased during the course of 1 year posttransplantation. The increase commenced after the completion of antiviral prophylaxis, and these T cells tended to be terminally differentiated effector cells. Based on this small cohort, these data suggest that even in the absence of disease, antigenic exposure may continually shape the CMV‐responsive T cell population posttransplantation.
Cocaine exposure enhances permissiveness of quiescent T cells to HIV infection

In vivo and in vitro exposure to stimulants has been associated with increased levels of HIV infection in PBMCs. Among these lymphocyte subsets, quiescent CD4+ T cells make up the majority of circulating T cells in the blood. Others and we have demonstrated that HIV infects this population of cells inefficiently. However, minor changes in their cell state can render them permissive to infection, significantly impacting the viral reservoir. We have hypothesized that stimulants, such as cocaine, may perturb the activation state of quiescent cells enhancing permissiveness to infection. Quiescent T cells isolated from healthy human donors were exposed to cocaine and infected with HIV. Samples were harvested at different time‐points to assess the impact of cocaine on their susceptibility to infection at various stages of the HIV life cycle. Our data show that a 3‐day exposure to cocaine enhanced infection of quiescent cells, an effect that appears to be mediated by σ1R and D4R. Overall, our results indicate that cocaine‐mediated effects on quiescent T cells may increase the pool of infection‐susceptible T cells. The latter underscores the impact that stimulants have on HIV‐seropositive individuals and the challenges posed for treatment.
Assessment of Tocilizumab (Anti–Interleukin‐6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody‐Mediated Rejection and Transplant Glomerulopathy in HLA‐Sensitized Renal Allograft Recipients

Extending the functional integrity of renal allografts is the primary goal of transplant medicine. The development of donor‐specific antibodies (DSAs) posttransplantation leads to chronic active antibody‐mediated rejection (cAMR) and transplant glomerulopathy (TG), resulting in the majority of graft losses that occur in the United States. This reduces the quality and length of life for patients and increases cost. There are no approved treatments for cAMR. Evidence suggests the proinflammatory cytokine interleukin 6 (IL‐6) may play an important role in DSA generation and cAMR. We identified 36 renal transplant patients with cAMR plus DSAs and TG who failed standard of care treatment with IVIg plus rituximab with or without plasma exchange. Patients were offered rescue therapy with the anti–IL‐6 receptor monoclonal tocilizumab with monthly infusions and monitored for DSAs and long‐term outcomes. Tocilizumab‐treated patients demonstrated graft survival and patient survival rates of 80% and 91% at 6 years, respectively. Significant reductions in DSAs and stabilization of renal function were seen at 2 years. No significant adverse events or severe adverse events were seen. Tocilizumab provides good long‐term outcomes for patients with cAMR and TG, especially compared with historical published treatments. Inhibition of the IL‐6–IL‐6 receptor pathway may represent a novel approach to stabilize allograft function and extend patient lives.