Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1) produce unique ...toxicity profiles. The objective of this review was to identify patterns and incidence of immune-related adverse events (irAE) based on tumour type and ICI class.
Medline, EMBASE and COCHRANE databases were searched to identify prospective monotherapy trials of ICIs from 2003 to November 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR),χ2 tests and multivariable regression models were used to analyse for effect size and associations.
We identified 48 trials (6938 patients), including 26 CTLA-4, 17 PD-1, 2 PD-L1 trials, and 3 studies tested both CTLA-4 and PD-1. Grade 3/4 irAE were more common with CTLA-4 mAbs compared with PD-1 (31% versus 10%). All grades colitis (OR 8.7, 95% CI 5.8–12.9), hypophysitis (OR 6.5, 95% CI 3.0–14.3) and rash (OR 2.0, 95% CI 1.8–2.3) were more frequent with CTLA-4 mAbs; whereas pneumonitis (OR 6.4, 95% CI 3.2–12.7), hypothyroidism (OR 4.3, 95% CI 2.9–6.3), arthralgia (OR 3.5, 95% CI 2.6–4.8) and vitiligo (OR 3.5, 95% CI 2.3–5.3) were more common with PD-1 mAbs. Comparison of irAE from the three most studied tumour types in PD-1 mAbs trials melanoma (n = 2048), non-small-cell lung cancer (n = 1030) and renal cell carcinoma (n = 573) showed melanoma patients had a higher frequency of gastrointestinal and skin irAE and lower frequency of pneumonitis.
CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumour-dependent irAE profiles may be identified as data emerge from ICI trials.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background The necessity of routine sub-nipple biopsy was uncertain, and the role of preoperative magnetic resonance imaging (MRI) in detecting nipple invasion in patients who have been ...selected for nipple-sparing mastectomy (NSM) has not been adequately evaluated. Methods We retrospectively collected and analyzed the medical and surgical records of 434 patients with primary operable breast cancer who met the criteria for NSM and underwent breast surgery during the period January 2011 to December 2015. Patients were stratified into three risk groups (low, intermediate, and high) according to tumor size and tumor-to-nipple distance. Results Among the 434 patients in this study, 29 (6.7%) had occult invasion of the nipple-areola complex (NAC). Sub-nipple biopsy had a sensitivity of 84.6%, a specificity of 100%, a false negative rate of 1.2%, a false positive rate of 0%, and an overall accuracy rate of 98.8% in confirming NAC invasion. The NAC invasion rate was 0% in the low-risk group, 5.1% in the intermediate-risk group, and 19.7% in the high-risk group (P<0.01). The overall NPV of preoperative MRI for predicting NAC invasion was 94.8%. Cost analysis revealed that the cost of NSM with sub-nipple biopsy was significantly higher than that of NSM alone, with a mean difference in cost of USD 238.5 (P<0.01). Conclusion The high negative predictive value of MRI for NAC invasion is useful for selection of patients receiving NSM. Sub-nipple biopsy is a reliable procedure to detect occult NAC invasion, however, routine use is not cost-effect for low risk patients.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
ReRAM is a promising next-generation nonvolatile memory (NVM) with fast write speed and low-power operation. However, ReRAM faces two major challenges in read operations: 1) low read yield due to ...wide resistance distribution and 2) the requirement of accurate bit line (BL) bias voltage control to prevent read disturbance. This study proposes two process-variation-tolerant schemes for current-mode read operation of ReRAM: parallel-series reference-cell (PSRC) and process-temperature-aware dynamic BL-bias (PTADB) schemes. These schemes are meant to improve the read speed and yield of ReRAM, while taking read disturbance into consideration. PSRC narrows the reference current distribution to achieve high read yield against resistance variation. PTADB achieves small fluctuations in BL bias voltage to prevent read disturbance, while providing rapid BL precharge speeds. This study fabricated a 4-Mb ReRAM macro to confirm the effectiveness of the proposed schemes for both SLC and MLC operations. The fastest sub-8-ns (7.2 ns) read-write random access time among megabit scaled embedded NVM macros has been demonstrated.
Sjögren's syndrome is a chronic and insidious autoimmune disease characterized by lymphocyte infiltration of exocrine glands. Patients typically present with dry eye, dry mouth, and other systemic ...manifestations. Currently, the available molecules and drug-delivery systems for the treatment of Sjögren's syndrome dry eye (SSDE) have limited efficacy since they are not specific to SSDE but to dry eye disease (DED) in general. The current treatment modalities are based on a trial-and-error approach using primarily topical agents. However, this approach gives time for the vicious cycle of DED to develop which eventually causes permanent damage to the lacrimal functional unit. Thus, there is a need for more individualized, specific, and effective treatment modalities for SSDE. The purpose of this article is to describe the current conventional SSDE treatment modalities and to expose new advances in ocular drug delivery for treating SSDE. A literature review of the pre-clinical and clinical studies published between 2016 and 2022 was conducted. Our current understanding of SSDE pathophysiology combined with advances in ocular drug delivery and novel therapeutics will allow the translation of innovative molecular therapeutics from the bench to the bedside.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We report a systematic comparison study of 3,5‐di(N‐carbazolyl)tetraphenylsilane (SimCP) and N,N′‐dicarbazolyl‐3,5‐benzene (mCP), which are used as the host materials for phosphorescent blue dopants ...in organic light‐emitting diodes (OLEDs). On the basis of photoexcitation emission spectroscopy, thermal stability analysis, photoelectron analysis, charge transport measurements, and molecular dynamics (MD) simulations, we conclude that the non‐π‐conjugated meta‐substituted triphenylsilyl moiety of SimCP exerts a unique hindering effect on the molecular packing characteristics in the condensed phase. The chemical origin of the superior performance of SimCP over mCP is revealed, and is expected to be helpful for the molecular design of effective host materials for enhancing the performance of blue phosphorescent OLEDs.
Two structurally similar host materials for electrophosphorescent blue dopants, mCP and SimCP (see figure), are systematically compared. The triphenylsilyl group on SimCP does not significantly alter the energy levels but prevents the close‐packing of the molecules in the condensed phase. In contrast, the mCP molecules tend to aggregate, as shown in the figure by the red‐shifting of the emission features, adversely affecting the singlet and triplet energy levels of the material.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
An effective-area photovoltaic efficiency of 1.27% in power conversion, excluding the grid metal contact area and under 1 sun, AM 1.5G conditions, has been obtained for the p-GaN/i-InGaN/n-GaN diode ...arrays epitaxially grown on (111)-Si. The short-circuit current density is 14.96 mA/cm
2
and the open-circuit voltage is 0.28 V. Enhanced light trapping acquired via multiple reflections within the strain and defect free III-nitride nanorod array structures and the short-wavelength responses boosted by the wide bandgap III-nitride constituents are believed to contribute to the observed enhancements in device performance.
Addition of cetuximab showed trend, but not significantly, to improve the therapeutic effects of gemcitabine and oxaliplatin combination for advanced biliary tract cancer in current randomized phase ...II trial. The trend of improvement did not correlate with KRAS mutation status. Biomarkers finding for selecting patients who will benefit most from anti-EGFR targeted therapy is warranted.
Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown.
ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1 : 1 to receive GEMOX (800 mg/m2 gemcitabine and 85 mg/m2 oxaliplatin) or C-GEMOX (500 mg/m2 cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR).
The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P = 0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P = 0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS.
Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status.
This study is registered at ClinicalTrials.gov (NCT01267344). All patients gave written informed consent.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A novel avian influenza A(H7N9) virus causing human infection emerged in February 2013 in China. To elucidate the mechanism of interspecies transmission, we compared the signature amino acids of ...avian influenza A(H7N9) viruses from human and non-human hosts and analysed the reassortants of 146 influenza A(H7N9) viruses with full genome sequences. We propose a genetic tuning procedure with continuous amino acid substitutions and reassorting that mediates host adaptation and interspecies transmission. When the early influenza A(H7N9) virus, containing ancestor haemagglutinin (HA) and neuraminidase (NA) genes similar to A/Shanghai/05 virus, circulated in waterfowl and transmitted to terrestrial poultry, it acquired an NA stalk deletion at amino acid positions 69 to 73. Then, receptor binding preference was tuned to increase the affinity to human-like receptors through HA G186V and Q226L mutations in terrestrial poultry. Additional mammalian adaptations such as PB2 E627K were selected in humans. The continual reassortation between H7N9 and H9N2 viruses resulted in multiple genotypes for further host adaptation. When we analysed a potential association of mutations and reassortants with clinical outcome, only the PB2 E627K mutation slightly increased the case fatality rate. Genetic tuning may create opportunities for further adaptation of influenza A(H7N9) and its potential to cause a pandemic.
Polycrystalline (Cu1-xZnx)2OSeO3 (0≤x≤0.2) samples were synthesized using solid-state reaction and characterized by X-ray diffraction (XRD). The effect of Zn doping upon saturation magnetization (MS) ...indicates that the Zn favors to occupying Cu(II) square pyramidal crystallographic site. The AC susceptibility (χ'ac) was measured at various temperatures (χ'ac-T) and magnetic field strengths (χ'ac-H). The Zn doping concentration is found to affect greatly the M-T and χ'ac-T. The skyrmion phase has been inferred from the χ'ac-H data, and then indicated within the H-T phase diagrams for various Zn doping concentrations. The striking and unexpected observation is that the skyrmion phase region becomes split upon Zn doping concentration. Interestingly, second conical boundary accompanied by second skyrmion phase was also observed from dχ'ac/dH vs. H curves. Atomic site disorder created by the chemical doping modulates the delicate magnetic interactions via change in the Dzyaloshinskii-Moriya (DM) vector of distorted Cu(II) square pyramidal, thereby splitting of skyrmion phase might occur. These findings illustrate the potential of using chemical and atomic modification for tuning the temperature and field dependence of skyrmion phase of Cu2OSeO3.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The effects of external (hydrostatic) compression and internal (chemical) expansion on the skyrmion phase have been investigated in Cu2OSeO3 single crystal and Cu2OSe1−xTexO3 (0 x 0.2) ...polycrystalline samples respectively. Under external pressure, the ferrimagnetic temperature TC ~ 57 K is increased with a positive rate (dTC /dP = 0.27 K kbar−1). The skyrmion zone enclosed in the H-T phase diagram is enlarged and shifted to high temperatures for Cu2OSeO3 single crystal. Consistently, the TC decreases with a negative rate (dTC /dx = −15.5 K/x) in Cu2OSe1−xTexO3 (0 x 0.2) and the skyrmion zone is suppressed and shifted to the low temperature side; complete disappearance of the skyrmion phase has been noted for x = 0.2. These observed results are explained to be related to the local crystal structure, namely, inter-atomic bond lengths and bond angles that modulate the strengths of competing Heisenberg exchange and Dzyaloshinsky-Moriya (DM) interactions. This approach to tuning the skyrmion ground state by external and chemical pressures might be useful for designing of spintronics devices.
PDF
