•This special article provides key recommendations on the immunotherapy treatments of renal cell carcinoma.•Recommendations are based on available scientific data and the authors' collective expert ...opinion.•Authorship includes a multidisciplinary group of renal carcinoma experts.
Highlights • Evasion of immune surveillance, a process defined immune-editing, leads to RCC malignant progression. • The PD-1/PD-L1 axis inhibition by targeted-antibodies, increases T-cell ...proliferation and anti-tumor activity. • PD-1 and PD-L1 inhibitors have been tested in RCC, alone or combined with anti-VEGF/VEGFR drugs or other immunotherapies. • We discuss the role of PD-1/PD-L1 in RCC, focusing on current clinical studies and future perspectives.
AlphaFold2 (AF2) has revolutionized the field of protein structural prediction. Here, we test its ability to predict the tertiary and quaternary structure of a previously undescribed scaffold with ...new folds and unusual architecture, the monotopic membrane protein caveolin-1 (CAV1). CAV1 assembles into a disc-shaped oligomer composed of 11 symmetrically arranged protomers, each assuming an identical new fold, and contains the largest parallel β-barrel known to exist in nature. Remarkably, AF2 predicts both the fold of the protomers and the interfaces between them. It also assembles between seven and 15 copies of CAV1 into disc-shaped complexes. However, the predicted multimers are energetically strained, especially the parallel β-barrel. These findings highlight the ability of AF2 to correctly predict new protein folds and oligomeric assemblies at a granular level while missing some elements of higher-order complexes, thus positing a new direction for the continued development of deep-learning protein structure prediction approaches.
Compressive sensing (CS) has recently been demonstrated as an enabling technology for hyperspectral sensing on remote and autonomous platforms. The power, on-board storage, and computation ...requirements associated with the high dimensionality of hyperspectral images (HSI) are still limiting factors for many applications. A recent work has exploited the benefits of CS to perform HSI classification directly in the compressively sensed band domain (CSBD). Since the required number of compressively sensed bands (CSBs) needed to achieve full band performance varies with the complexity of an image scene, this article presents a progressive band processing (PBP) approach, called progressive CSB classification (PCSBC), to adaptively determine an appropriate number of CSBs required to achieve full band performance, while also providing immediate feedback from progressions of class classification predictions carried out by PCSBC. By taking advantage of PBP, new progression metrics and stopping criteria are also designed for PCSBC. Four real-world HSIs are used to demonstrate the utility of PCSBC.
The recent Zika virus (ZIKV) epidemic has been linked to unusual and severe clinical manifestations including microcephaly in fetuses of infected pregnant women and Guillian-Barré syndrome in adults. ...Neutralizing antibodies present a possible therapeutic approach to prevent and control ZIKV infection. Here we present a 6.2 Å resolution three-dimensional cryo-electron microscopy (cryoEM) structure of an infectious ZIKV (strain H/PF/2013, French Polynesia) in complex with the Fab fragment of a highly therapeutic and neutralizing human monoclonal antibody, ZIKV-117. The antibody had been shown to prevent fetal infection and demise in mice. The structure shows that ZIKV-117 Fabs cross-link the monomers within the surface E glycoprotein dimers as well as between neighbouring dimers, thus preventing the reorganization of E protein monomers into fusogenic trimers in the acidic environment of endosomes.
Objective: To assess the potential clinical use, particularly in modulating stress, of changes in the cardiovascular and respiratory systems induced by music, specifically tempo, rhythm, melodic ...structure, pause, individual preference, habituation, order effect of presentation, and previous musical training. Design: Measurement of cardiovascular and respiratory variables while patients listened to music. Setting: University research laboratory for the study of cardiorespiratory autonomic function. Patients: 12 practising musicians and 12 age matched controls. Interventions: After a five minute baseline, presentation in random order of six different music styles (first for a two minute, then for a four minute track), with a randomly inserted two minute pause, in either sequence. Main outcome measures: Breathing rate, ventilation, carbon dioxide, RR interval, blood pressure, mid-cerebral artery flow velocity, and baroreflex. Results: Ventilation, blood pressure, and heart rate increased and mid-cerebral artery flow velocity and baroreflex decreased with faster tempi and simpler rhythmic structures compared with baseline. No habituation effect was seen. The pause reduced heart rate, blood pressure, and minute ventilation, even below baseline. An order effect independent of style was evident for mid-cerebral artery flow velocity, indicating a progressive reduction with exposure to music, independent of style. Musicians had greater respiratory sensitivity to the music tempo than did non-musicians. Conclusions: Music induces an arousal effect, predominantly related to the tempo. Slow or meditative music can induce a relaxing effect; relaxation is particularly evident during a pause. Music, especially in trained subjects, may first concentrate attention during faster rhythms, then induce relaxation during pauses or slower rhythms.
•VEGFR-TKIs + PD-1 ICIs combinations are a new first-line standard of care in mRCC.•The benefit of VEGFR-TKIs + ICIs is unclear in IMDC favorable mRCC patients.•We performed a meta-analysis to assess ...VEGFR-TKIs + ICIs vs. sunitinib in IMDC favorable patients.•VEGFR-TKI + ICI combinations improved PFS as first-line therapy.•No OS advantage was observed in this subgroup.
Combinations of PD-1/PD-L1 immune checkpoint inhibitors (ICI) with VEGFR-TKIs as first-line therapy significantly improve outcomes of metastatic renal cell carcinoma (mRCC) patients. The benefit of these combinations is well evident in the IMDC intermediate- and poor-risk population, but remains unclear in the subgroup of patients with favorable prognosis. Our meta-analysis aims at evaluating whether the addition of ICIs to VEGFR-TKIs is able to improve the outcome compared to VEGFR-TKIs alone in mRCC patients with favorable prognosis.
This meta-analysis searched MEDLINE/PubMed, the Cochrane Library and ASCO Meeting abstracts for randomized clinical trials (RCTs) testing the combination of VEGFR-TKI + ICI in mRCC. Data extraction was conducted according to the PRISMA statement. Summary hazard ratio (HR) was calculated using random- or fixed-effects models, depending on studies heterogeneity.
Four RCTs were selected. VEGFR-TKI + ICI combinations improved PFS compared to sunitinib (fixed-effect, HR = 0.63; p < 0.00001). However, VEGFR-TKI + ICI combinations did not significantly prolong OS (fixed-effect; HR = 0.99; 95% CI 0.74–1.33; p = 0.95).
VEGFR-TKI + ICI combinations improved PFS but not OS as first-line therapy for mRCC patients with favorable IMDC prognosis. Longer follow-up and further studies will increase the power of our analysis, suggesting the best first-line therapy for mRCC patients with favorable prognosis.
Despite offering significant clinical benefits in advanced renal-cell carcinoma (RCC), the effectiveness of targeted therapies eventually declines with the development of resistance. Defining optimal ...sequences of therapy is therefore the focus of much current research. There is also evidence that treatment 're-challenge' may be an effective strategy in some patients. We review evidence to evaluate whether sunitinib may have value as re-challenge therapy in patients who have progressed on prior targeted therapy with sunitinib and/or an alternative tyrosine kinase inhibitor or mammalian target of rapamycin inhibitor. Re-challenge with sunitinib appears to be of clinical benefit, thus representing a feasible therapeutic option for patients with advanced RCC who are refractory to other treatments and are able to receive further therapy. These observations support hypotheses that resistance to targeted agents is transient and can be at least partially reversed by re-introduction of the same agent after a treatment break. Median progression-free survival durations appear to be shorter and response rates lower on re-challenge than following initial treatment, although a wider interval between treatments appears to increase response to sunitinib re-challenge.
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