STARBOARD: encorafenib + binimetinib + pembrolizumab for first-line metastatic/unresectable BRAF V600-mutant melanoma

Despite the significant progress in the treatment of unresectable or metastatic BRAF V600-mutant melanoma, there remains two primary treatment options: targeted therapy and immunotherapy. Targeted therapy or immunotherapy alone is associated with efficacy limitations including efficacy limited to select patient subsets. With separate mechanisms of action and different response patterns, the combination of targeted agents and immunotherapy to treat patients with BRAF V600-mutant melanoma may further improve patient outcomes. Current treatment guidelines recommend treatment with targeted agents alone, immunotherapy, or the combination of targeted agents and immunotherapy. The randomized, double-blind STARBOARD trial aims to evaluate efficacy and safety of encorafenib, binimetinib and pembrolizumab in treatment-naive patients with metastatic or unresectable locally advanced BRAF V600-mutant melanoma in comparison to pembrolizumab

Literature search on risk factors for sarcoma: PubMed and Google Scholar may be complementary sources

<p>Abstract</p> <p>Background</p> <p>Within the context of a European network dedicated to the study of sarcoma the relevant literature on sarcoma risk factors was collected by searching PubMed and Google Scholar, the two information storage and retrieval databases which can be accessed without charge. The present study aims to appraise the relative proficiency of PubMed and Google Scholar.</p> <p>Findings</p> <p>Unlike PubMed, Google Scholar does not allow a choice between "Human" and "Animal" studies, nor between "Classical" and other types of studies. As a result, searches with Google Scholar produced high numbers of citations that have to be filtered. Google Scholar resulted in a higher sensitivity (proportion of relevant articles, meeting the search criteria), while PubMed in a higher specificity (proportion of lower quality articles not meeting the criteria, that are not retrieved). Concordance between Google Scholar and PubMed was as low as 8%.</p> <p>Conclusions</p> <p>This study focused just on one topic. Although further studies are warranted, PM and GS appear to be complementary and their integration could greatly improve the search of references in medical research.</p

AIDS-Kaposi Sarcoma and Classic Kaposi Sarcoma: are different ultrasound patterns related to different variants?

<p>Abstract</p> <p>Background</p> <p>Kaposi Sarcoma (KS) is a malignancy of endothelial skin cells with multifocal localization on the skin, lymph nodes and visceral organs. Although all clinical variants are associated with HHV-8 infection, specific differences in the clinical onset and in the natural history of AIDS-KS and Classic-KS have been described. The present randomised prospective-observational study aimed to investigate whether the ultrasound pattern and color Doppler flow imaging of vascularisation of skin lesions of patients with Classic KS (CKS) or AIDS-KS could provide useful information to the evaluation of clinical activity of the disease.</p> <p>Methods</p> <p>Cutaneous lesions of 24 patients with histologically confirmed KS were investigated using very high frequency ultrasound probes; 16 patients had CKS and 8 had AIDS-KS. HHV-8 infection was confirmed in all patients by investigating the specific humoral response to viral antigens. Immunological and virological parameters were also assessed to monitor HIV or HHV-8 viral infection. For each patient, a target skin lesion was selected on the basis of size (diameter from 0.4 to 2 cm). Each lesion was analyzed in terms of size, depth and color Doppler pattern.</p> <p>Results</p> <p>The B-mode ultrasound patterns of skin lesions did not differ when comparing CKS patients to AIDS-KS patients, whereas the color Doppler signal, which is associated with vascular activity, was detected in the KS lesions of 6/8 AIDS-KS patients (75.0%) and in 2/16 CKS (16,7%); the latter two patients showed a clinically progressive and extensive disease stage (IV B).</p> <p>Conclusions</p> <p>Our preliminary results suggest that small cutaneous KS lesions - in both CKS and AIDS-KS patients- display similar B-mode ultrasound patterns ( hypoechoic, well defined, superficial lesions). However, the color Doppler signal, which is associated with endothelial activity and angiogenesis, which play a substantial role in KS progression, could constitute a useful tool for evaluating disease activity.</p

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years

Providing person-centered palliative care in conflict-affected populations in the Middle East: What matters to patients with advanced cancer and families including refugees?

IntroductionUniversal health coverage highlights palliative care as an essential component of health services. However, it is unclear what constitutes person-centered care in populations affected by conflict, as they may have specific concerns in the dimensions of physical, emotional, social, and spiritual wellbeing. This study aimed to identify what matters to patients with advanced cancer and family caregivers in Jordan including refugees, to inform appropriate person-centered assessment and palliative care in conflict-affected populations.MethodsCross-sectional face-to-face, semi-structured interviews were conducted at two sites in Amman. Adult patients with advanced cancer and family caregivers were purposively sampled to maximize diversity and representation. Interviews were digitally audio recorded, anonymized, and transcribed verbatim for thematic analysis.FindingsFour themes were generated from 50 patients (22 refugees; 28 Jordanians) and 20 caregivers (7 refugees; 13 Jordanians) (1). Information, communication, and decision-making. Truth-telling and full disclosure from clinicians was valued, and participants expressed concerns that information was not shared in case patients would disengage with treatment. (2) Priorities and concerns for care and support. Participants’ top priority remained cure and recovery (which was viewed as possible). Other priorities included returning to their “normal” life and their “own” country, and to continue contributing to their family. (3) Role of spirituality and Islam. Most participants had strong faith in God and felt that having faith could comfort them. For refugees whose social network was fractured due to being away from home country, prayer and Quran reading became particularly important. (4) Unmet support needs of family caregivers. Family caregivers were affected physically and emotionally by worrying about and caring for the patients. They needed support and training, but often could not access this.DiscussionTruth-telling is highly valued and essential to achieving person-centered care and informed decision-making. This study also reveals specific concerns in conflict-affected populations, reflecting the experience of prior losses and fracturing of existing social networks and support. The role of religion is crucial in supporting refugee communities, and consideration should be paid to the needs of patients and caregivers when caring for a patient at home without access to their communities of origin and the support they accessed

Rate and determinants of treatment response to different antiretroviral combination strategies in subjects presenting at HIV-1 diagnosis with advanced disease

<p>Abstract</p> <p>Background</p> <p>The optimal therapeutic strategies for patients presenting with advanced disease at HIV-1 diagnosis are as yet incompletely defined.</p> <p>Methods</p> <p>All patients presenting at two outpatient clinics in 2000-2009 with an AIDS-defining clinical condition or a CD4+ T cell count < 200/μL at HIV-1 diagnosis were analyzed for the presence of combined immunovirological response, defined by the concomitant presence of an absolute number of CD4+ T cells > 200 cells/μL and a plasma HIV-1 RNA copy number < 50/mL after 12 months of HAART.</p> <p>Results</p> <p>Among 102 evaluable patients, first-line regimens were protease inhibitors [PI]-based in 78 cases (77%) and efavirenz-based in 24 cases (23%). The overall response rate was 65% (95% CI: 55-74), with no differences by gender, age, nationality, route of transmission, hepatitis virus coinfections, presence of AIDS-defining clinical events, baseline HIV-1 viral load, or type of regimen (response rates with PI-based and efavirenz-based therapy: 63% and 71%, respectively, p = 0.474). Response rate was significantly better with higher baseline CD4+ T cell counts (78% with CD4+ ≥ 100/μL, compared to 50% with CD4+ < 100/μL; odds ratio: 3.5; 95% CI: 1.49-8.23, p = 0.003). Median time on first-line antiretroviral therapy was 24 months (interquartile range: 12-48). Switch to a second line treatment occurred in 57% of patients, mainly for simplification (57%), and was significantly more common with PI-based regimens [adjusted hazard ratios (AHR) with respect to efavirenz-based regimens: 3.88 for unboosted PIs (95% CI: 1.40-10.7, p = 0.009) and 4.21 for ritonavir-boosted PI (95%CI 1.7-10.4, p = 0.002)] and in older subjects (≥ 50 years) (AHR: 1.83; 95% CI: 1.02-3.31, p = 0.044). Overall mortality was low (3% after a median follow up of 48 months).</p> <p>Conclusions</p> <p>Our data indicate that a favorable immunovirological response is possible in the majority of naive patients presenting at HIV-1 diagnosis with AIDS or low CD4+ T cell counts, and confirm that starting HAART with a more compromised immune system may be associated with a delayed and sometimes partial immune recovery. Simpler regimens may be preferable in this particular population.</p

Transcriptomics in Interferon-α-Treated Patients Identifies Inflammation-, Neuroplasticity- and Oxidative Stress-Related Signatures as Predictors and Correlates of Depression

Owing to the unique opportunity to assess individuals before and after they develop depression within a short timeframe, interferon-α (IFN-α) treatment for chronic hepatitis C virus (HCV) infection is an ideal model to identify molecular mechanisms relevant to major depression, especially in the context of enhanced inflammation. Fifty-eight patients were assessed prospectively, at baseline and monthly over 24 weeks of IFN-α treatment. New-onset cases of depression were determined using the Mini International Neuropsychiatric Interview (MINI). Whole-blood transcriptomic analyses were conducted to investigate the following: (1) baseline gene expression differences associated with future development of IFN-α-induced depression, before IFN-α, and (2) longitudinal gene expression changes from baseline to weeks 4 or 24 of IFN-α treatment, separately in those who did and did not develop depression. Transcriptomics data were analyzed using Partek Genomics Suite (1.4-fold, FDR adjusted pless than or equal to0.05) and Ingenuity Pathway Analysis Software. Twenty patients (34%) developed IFN-α-induced depression. At baseline, 73 genes were differentially expressed in patients who later developed depression compared with those who did not. After 4 weeks of IFN-α treatment, 592 genes were modulated in the whole sample, representing primarily IFN-α-responsive genes. Substantially more genes were modulated only in patients who developed depression (n=506, compared with n=70 in patients who did not), with enrichment in inflammation-, neuroplasticity- and oxidative stress-related pathways. A similar picture was observed at week 24. Our data indicate that patients who develop IFN-α-induced depression have an increased biological sensitivity to IFN-α, as shown by larger gene expression changes, and specific signatures both as predictors and as correlates

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes

Ejecta Evolution Following a Planned Impact into an Asteroid: The First Five Weeks

The impact of the DART spacecraft into Dimorphos, moon of the asteroid Didymos, changed Dimorphos' orbit substantially, largely from the ejection of material. We present results from twelve Earth-based facilities involved in a world-wide campaign to monitor the brightness and morphology of the ejecta in the first 35 days after impact. After an initial brightening of ~1.4 magnitudes, we find consistent dimming rates of 0.11-0.12 magnitudes/day in the first week, and 0.08-0.09 magnitudes/day over the entire study period. The system returned to its pre-impact brightness 24.3-25.3 days after impact through the primary ejecta tail remained. The dimming paused briefly eight days after impact, near in time to the appearance of the second tail. This was likely due to a secondary release of material after re-impact of a boulder released in the initial impact, through movement of the primary ejecta through the aperture likely played a role.Comment: 16 pages, 5 Figures, accepted in the Astrophysical Journal Letters (ApJL) on October 16, 202

Incorporating biodiversity responses to land use change scenarios for preventing emerging zoonotic diseases in areas of unknown host-pathogen interactions

The need to reconcile food production, the safeguarding of nature, and the protection of public health is imperative in a world of continuing global change, particularly in the context of risks of emerging zoonotic disease (EZD). In this paper, we explored potential land use strategies to reduce EZD risks using a landscape approach. We focused on strategies for cases where the dynamics of pathogen transmission among species were poorly known and the ideas of “land-use induced spillover” and “landscape immunity” could be used very broadly. We first modeled three different land-use change scenarios in a region of transition between the Cerrado and the Atlantic Forest biodiversity hotspots. The land-use strategies used to build our scenarios reflected different proportions of native vegetation cover, as a proxy of habitat availability. We then evaluated the effects of the proportion of native vegetation cover on the occupancy probability of a group of mammal species and analyzed how the different land-use scenarios might affect the distribution of species in the landscape and thus the risk of EZD. We demonstrate that these approaches can help identify potential future EZD risks, and can thus be used as decision-making tools by stakeholders, with direct implications for improving both environmental and socio-economic outcomes