The treatment paradigm for metastatic hormone-sensitive prostate cancer (mHSPC) patients is evolving. PET/CT now offers improved sensitivity and accuracy in staging. Recent randomized trial data ...supports escalated hormone therapy, local primary tumor therapy, and metastasis-directed therapy. The impact of combining such therapies into a multimodal approach is unknown. This Phase II single-arm clinical trial sponsored and funded by Veterans Affairs combines local, metastasis-directed, and systemic therapies to durably render patients free of detectable disease off active therapy.
Patients with newly-diagnosed M1a/b prostate cancer (PSMA PET/CT staging is permitted) and 1-5 radiographically visible metastases (excluding pelvic lymph nodes) are undergoing local treatment with radical prostatectomy, limited duration systemic therapy for a total of six months (leuprolide, abiraterone acetate with prednisone, and apalutamide), metastasis-directed stereotactic body radiotherapy (SBRT), and post-operative fractionated radiotherapy if pT ≥ 3a, N1, or positive margins are present. The primary endpoint is the percent of patients achieving a serum PSA of < 0.05 ng/mL six months after recovery of serum testosterone ≥150 ng/dL. Secondary endpoints include time to biochemical progression, time to radiographic progression, time to initiation of alternative antineoplastic therapy, prostate cancer specific survival, health related quality-of-life, safety and tolerability.
To our knowledge, this is the first trial that tests a comprehensive systemic and tumor directed therapeutic strategy for patients with newly diagnosed oligometastatic prostate cancer. This trial, and others like it, represent the critical first step towards curative intent therapy for a patient population where palliation has been the norm.
Clinicaltrials.gov identifier: NCT03298087 (registration date: September 29, 2017).
Objective: Xerostomia is a frequent and potentially debilitating toxicity of radiotherapy (XRT) for cancers of the head and neck. This report describes the use of acupuncture as palliation for such ...patients.
Methods and Materials: Eighteen patients with xerostomia refractory to pilocarpine therapy after XRT for head and neck malignancy were offered acupuncture as palliation. All patients are without evidence of cancer recurrence at the primary site. Acupuncture was provided to three auricular points and one digital point bilaterally, with electrostimulation used variably. The Xerostomia Inventory (XI) was administered retrospectively to provide an objective measure of efficacy.
Results: Acupuncture contributed to relief from xerostomia to varying degrees. Palliative effect as measured by the XI varied from nil to robust (pre- minus post- therapy values of over 20 points). Nine patients had benefit of over 10 points on the XI.
Conclusions: Acupuncture reduces xerostomia in some patients who are otherwise refractory to best current management.
Short peptide sequences within the microtubule binding domain of the protein Tau are proposed to be core nucleation sites for formation of amyloid fibrils displaying the paired helical filament (PHF) ...morphology characteristic of neurofibrillary tangles. To study the structure of these proposed nucleation sites, we analyzed the x-ray diffraction patterns from the assemblies formed by a variety of PHF/tau-related peptide constructs containing the motifs VQIINK (PHF6*) in the second repeat and VQIVYK (PHF6) in the third repeat of tau. Peptides included: tripeptide acetyl-VYK-amide (AcVYK), tetrapeptide acetyl-IVYK-amide (AcPHF4), hexapeptide acetyl-VQIVYK-amide (AcPHF6), and acetyl-GK
VQIINKLDLSNVQKDNIKHGS
VQIVYKPVDLSKVT-amide (AcTR4). All diffraction patterns showed reflections at spacings of 4.7
Å, 3.8
Å, and ∼8–10
Å, which are characteristic of an orthogonal unit cell of
β-sheets having dimensions
a
=
9.4
Å,
b
=
6.6
Å, and
c
=
∼8–10
Å (where
a,
b, and
c are the lattice constants in the H-bonding, chain, and intersheet directions). The sharp 4.7
Å reflections indicate that the
β-crystallites are likely to be elongated along the H-bonding direction and in a cross-
β conformation. The assembly of the AcTR4 peptide, which contains both the PHF6 and PHF6* motifs, consisted of twisted sheets, as indicated by a unique fanning of the diffuse equatorial scattering and meridional accentuation of the (210) reflection at 3.8
Å spacing. The diffraction data for AcVYK, AcPHF4, and AcPHF6 all were consistent with ∼50
Å-wide tubular assemblies having double-walls, where
β-strands constitute the walls. In this structure, the peptides are H-bonded together in the fiber direction, and the intersheet direction is radial. The positive-charged lysine residues face the aqueous medium, and tyrosine-tyrosine aromatic interactions stabilize the intersheet (double-wall) layers. This particular contact, which may be involved in PHF fibril formation, is proposed here as a possible aromatic target for anti-tauopathy drugs.
We studied fibril formation in a family of peptides based on PHF6 (VQIVYK), a short peptide segment found in the microtubule binding region of tau protein. N-Acetylated peptides AcVYK-amide (AcVYK), ...AcIVYK-amide (AcPHF4), AcQIVYK-amide (AcPHF5), and AcV-QIVYK-amide (AcPHF6) rapidly formed straight filaments in the presence of 0.15 m NaCl, each composed of two laterally aligned protofilaments ∼5 nm in width. X-ray fiber diffraction showed the omnipresent sharp 4.7-Å reflection indicating that the scattering objects are likely elongated along the hydrogen-bonding direction in a cross-β conformation, and Fourier transform IR suggested the peptide chains were in a parallel (AcVYK, AcPHF6) or antiparallel (AcPHF4, AcPHF5) β-sheet configuration. The dipeptide N-acetyl-YK-amide (AcYK) formed globular structures ∼200 nm to 1 μm in diameter. The polymerization rate, as measured by thioflavin S binding, increased with the length of the peptide going from AcYK → AcPHF6, and peptides that aggregated most rapidly displayed CD spectra consistent with β-sheet structure. There was a 3-fold decrease in rate when Val was substituted for Ile or Gln, nearly a 10-fold decrease when Ala was substituted for Tyr, and an increase in polymerization rate when Glu was substituted for Lys. Twisted filaments, composed of four laterally aligned protofilaments (9–19 nm width, ∼90 nm half-periodicity), were formed by mixing AcPHF6 with AcVYK. Taken together these results suggest that the core of PHF6 is localized at VYK, and the interaction between small amphiphilic segments of tau may initiate nucleation and lead to filaments displaying paired helical filament morphology.
Bluetooth Haartsen, Jaap; Naghshineh, Mahmoud; Inouye, Jon ...
Mobile computing and communications review,
10/1998, Letnik:
2, Številka:
4
Journal Article
A few years ago it was recognized that the vision of a truly low-cost, low-power radio-based cable replacement was feasible. Such a ubiquitous link would provide the basis for portable devices to ...communicate together in an ad hoc fashion by creating
personal area networks
which have similar advantages to their office environment counterpart - the local area network (LAN). Bluetooth is an effort by a consortium of companies to design a royalty free technology specification enabling this vision. This article describes the vision and goals of the Bluetooth program and introduces the radio-based technology.
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