Objective
We undertook this phase III study to evaluate baricitinib, an orally administered JAK‐1/JAK‐2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in ...patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease‐modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs.
Methods
A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24.
Results
The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment‐emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX.
Conclusion
Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.
Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly ...improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. Importantly, cancer patients with low plasma histamine levels had a more than tripled objective response rate to anti-PD-1 treatment compared with patients with high plasma histamine. Altogether, pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy.
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•Histamine binding of HRH1 on macrophages induces an immunosuppressive phenotype•H1-antihistamine treatment enhances immunotherapy response•Allergic reaction promotes immune evasion and resistance to immunotherapy•High histamine and HRH1 levels correlate with poor immunotherapy response in patients
Li et al. investigate how cancer cells evade immune attack and resist immunotherapies. Cancer cell-derived or allergy-released histamine binds to HRH1 on tumor-associated macrophages that suppress CD8+ T cell function, accelerate tumor growth, and confer immunotherapy resistance. H1-antihistamines counteract histamine-mediated immunosuppression, reinforce antitumor immunity, and significantly enhance immunotherapy response.
Hydrogen sulfide (H2S), an endogenous signaling gaseous molecule, is involved in various physiological activities, including vessel relaxation, regulation of cellular bioenergetics, inflammation, and ...angiogenesis. By using xenograft orthotopic implantation of prostate cancer PC3 cells and subsequently comparing bone metastatic with primary tumor‐derived cancer cells, we find that H2S‐producing enzyme cystathionine γ‐lyase (CTH) is upregulated in bone‐metastatic PC3 cells. Clinical data further reveal that the expression of CTH is elevated in late‐stage prostate cancer patients, and higher CTH expression correlates with poor survival from The Cancer Genome Atlas (TCGA) prostate cancer RNA‐seq datasets. CTH promotes NF‐κB nuclear translocation through H2S‐mediated sulfhydration on cysteine‐38 of the NF‐κB p65 subunit, resulting in increased IL‐1β expression and H2S‐induced cell invasion. Knockdown of CTH in PC3 cells results in the suppression of tumor growth and distant metastasis, while overexpression of CTH in DU145 cells promotes primary tumor growth and lymph node metastasis in the orthotopic implanted xenograft mouse model. Together, our findings provide evidence that CTH generated H2S promotes prostate cancer progression and metastasis through IL‐1β/NF‐κB signaling pathways.
Synopsis
Cystathionine‐γ‐lyase (CTH) and its catalyzed product hydrogen sulfide, a known gaseous transmitter, are dysregulated in prostate cancer. Increased CTH activity promotes cancer progression and metastasis via the sulfhydration of the NF‐κB subunit p65.
CTH induces H2S production to stimulate the sulfhydration of p65, promoting its nuclear translocation.
CTH‐dependent p65 sulfhydration triggers cell invasion via IL‐1β mediated signaling.
CTH promotes tumor growth, angiogenesis and lymphangiogenesis and distant metastasis in vivo.
CTH levels are elevated in late‐stage prostate cancer patients and negatively correlated with good prognosis.
Cystathionine‐γ‐lyase (CTH) and its catalyzed product hydrogen sulfide, a known gaseous transmitter, are dysregulated in prostate cancer. Increased CTH activity promotes cancer progression and metastasis via the sulfhydration of the NF‐κB subunit p65.
The transfer of whole mitochondria that occurs during cell contact has been found to support cancer progression. However, the regulatory role of mitochondria alone is difficult to elucidate due to ...the complex microenvironment. Currently, mitochondrial transplantation is an available approach for restoring mitochondrial function in mitochondrial diseases but remains unclear in breast cancer. Herein, effects of mitochondrial transplantation via different approaches in breast cancer were investigated.
Whole mitochondria (approximately 10.5 μg/ml) were transported into MCF-7 breast cancer cells via passive uptake or Pep-1-mediated delivery. Fresh mitochondria isolated from homeoplasmic 143B osteosarcoma cybrids containing mitochondrial DNA (mtDNA) derived from health individuals (Mito) or mtDNA with the A8344G mutation (Mito
) were conjugated with cell-penetrating peptide Pep-1 (P-Mito) or not conjugated prior to cell co-culture. Before isolation, mitochondria were stained with MitoTracker dye as the tracking label. After 3 days of treatment, cell viability, proliferation, oxidative stress, drug sensitivity to Doxorubicin/Paclitaxel and mitochondrial function were assessed.
Compared with P-Mito, a small portion of Mito adhered to the cell membrane, and this was accompanied by a slightly lower fluorescent signal by foreign mitochondria in MCF-7 cells. Both transplantations induced cell apoptosis by increasing the nuclear translocation of apoptosis-inducing factor; inhibited cell growth and decreased oxidative stress in MCF-7 cells; and increased the cellular susceptibility of both the MCF-7 and MDA-MB-231 cell lines to Doxorubicin and Paclitaxel. Mitochondrial transplantation also consistently decreased Drp-1, which resulted in an enhancement of the tubular mitochondrial network, but a distinct machinery through the increase of parkin and mitochondrial fusion proteins was observed in the Mito and P-Mito groups, respectively. Furthermore, although there were no differences in energy metabolism after transplantation of normal mitochondria, metabolism was switched to the energetic and glycolytic phenotypes when the mitochondria were replaced with dysfunctional mitochondria, namely, Mito
and P-Mito
, due to dramatically induced glycolysis and reduced mitochondrial respiration, respectively. Consequently, transplant-induced growth inhibition was abolished, and cell growth in the Mito
group was even higher than that in the control group.
This study reveals the antitumour potential of mitochondrial transplantation in breast cancer via distinct regulation of mitochondrial function.
This study evaluates patient-reported outcomes (PROs) in a double-blind, phase III study of baricitinib as monotherapy or combined with methotrexate (MTX) in patients with active rheumatoid arthritis ...(RA) with no or minimal prior conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and naïve to biological DMARDs.
Patients were randomized 4:3:4 to MTX administered once weekly (N = 210), baricitinib monotherapy (4 mg once daily (QD), N = 159), or combination of baricitinib (4 mg QD) and MTX (baricitinib + MTX, N = 215). PROs included the Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration of morning joint stiffness (MJS), worst joint pain, worst tiredness, Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA), Short Form 36 version 2, Acute (SF-36); and EuroQol 5-Dimensions (EQ-5D) Health State Profile. Comparisons were assessed with analysis of covariance (ANCOVA) and logistic regression models.
Compared to MTX, patients in both baricitinib groups reported greater improvement (p ≤ 0.01) in HAQ-DI, PtGA, pain, fatigue, worst join pain, SF-36 physical component score, and EQ-5D at weeks 24 and 52. For the SF-36 mental component score, patients in both baricitinib groups reported statistically significant improvements (p ≤ 0.01) at week 52 compared to MTX-treated patients. Statistically significant improvements (p ≤ 0.05) were observed with the WPAI-RA for the baricitinib groups vs. MTX at week 24 and for the WPAI-RA daily activity and work productivity measures for baricitinib + MTX at week 52.
In this study, baricitinib alone or in combination with MTX, when used as initial therapy, resulted in significant improvement compared to MTX in the majority of the pre-specified PRO measures.
ClinicalTrials.gov, NCT01711359 . Registered on 18 October 2012.
Five novel peptides (LPLF, WLQL, LPSW, VPGLAL, and LVGLPL) bearing dipeptidyl peptidase IV (DPP-IV) inhibitory activities were identified from the gastrointestinal enzymatic hydrolysate of ...soft-shelled turtle yolk (SSTY) proteins. Peptides were isolated separately using reversed-phase (RP) chromatography in parallel with off-line strong cation exchange (SCX) chromatography followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to determine sequences. Among these peptides, LPSW showed the highest DPP-IV inhibitory activity with an IC50 value of 269.7 ± 15.91 µM. The results of the pre-incubation experiment and the kinetic study of these peptides indicated that WLQL is a true inhibitor and its inhibition toward DPP-IV is of an uncompetitive model, while LPLF, LPSW, and VPGLAL are real-substrates and competitive inhibitors against DPP-IV. The DPP-IV inhibitory peptides derived from SSTY hydrolysate in study are promising in the management of hyperglycemia in Type 2 diabetes.
Polycystic ovary syndrome (PCOS) is a common endocrinopathy, characterized by chronic anovulation, hyperandrogenism, and multiple small subcapsular cystic follicles in the ovary during ...ultrasonography, and affects 5-10% of women of reproductive age. PCOS is frequently associated with insulin resistance (IR) accompanied by compensatory hyperinsulinemia and, therefore, presents an increased risk of type 2 diabetes mellitus (DM). The pathophysiology of PCOS is unclear, and many hypotheses have been proposed. Among these hypotheses, IR and hyperandrogenism may be the two key factors. The first line of treatment in PCOS includes lifestyle changes and body weight reduction. Achieving a 5-15% body weight reduction may improve IR and PCOS-associated hormonal abnormalities. For women who desire pregnancy, clomiphene citrate (CC) is the front-line treatment for ovulation induction. Twenty five percent of women may fail to ovulate spontaneously after three cycles of CC treatment, which is called CC-resistant PCOS. For CC-resistant PCOS women, there are many strategies to improve ovulation rate, including medical treatment and surgical approaches. Among the various surgical approaches, one particular surgical method, called laparoscopic ovarian drilling (LOD), has been proposed as an alternative treatment. LOD results in an overall spontaneous ovulation rate of 30-90% and final pregnancy rates of 13-88%. These benefits are more significant for women with CC-resistant PCOS. Although the intra- and post-operative complications and sequelae are always important, we believe that a better understanding of the pathophysiological changes and/or molecular mechanisms after LOD may provide a rationale for this procedure. LOD, mediated mainly by thermal effects, produces a series of morphological and biochemical changes. These changes include the formation of artificial holes in the very thick cortical wall, loosening of the dense and hard cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response, and the continuing leakage or drainage of "toxic" follicular fluid in these immature and growth-ceased pre-antral follicles. All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; the re-starting of normal follicular recruitment, development, and maturation, and finally, the normalization of the "hypothalamus-pituitary-ovary" axis and subsequent spontaneous ovulation. The detailed local and systematic changes in PCOS women after LOD are comprehensively reviewed in the current article.
Despite the popular use of dietary supplements during conventional cancer treatments, their impacts on the efficacies of prevalent immunotherapies, including immune-checkpoint therapy (ICT), are ...unknown. Surprisingly, our analyses of electronic health records revealed that ICT-treated patients with cancer who took vitamin E (VitE) had significantly improved survival. In mouse models, VitE increased ICT antitumor efficacy, which depended on dendritic cells (DC). VitE entered DCs via the SCARB1 receptor and restored tumor-associated DC functionality by directly binding to and inhibiting protein tyrosine phosphatase SHP1, a DC-intrinsic checkpoint. SHP1 inhibition, genetically or by VitE treatment, enhanced tumor antigen cross-presentation by DCs and DC-derived extracellular vesicles (DC-EV), triggering systemic antigen-specific T-cell antitumor immunity. Combining VitE with DC-recruiting cancer vaccines or immunogenic chemotherapies greatly boosted ICT efficacy in animals. Therefore, combining VitE supplement or SHP1-inhibited DCs/DC-EVs with DC-enrichment therapies could substantially augment T-cell antitumor immunity and enhance the efficacy of cancer immunotherapies.
The impacts of nutritional supplements on responses to immunotherapies remain unexplored. Our study revealed that dietary vitamin E binds to and inhibits DC checkpoint SHP1 to increase antigen presentation, prime antitumor T-cell immunity, and enhance immunotherapy efficacy. VitE-treated or SHP1-silenced DCs/DC-EVs could be developed as potent immunotherapies. This article is highlighted in the In This Issue feature, p. 1599.
Neoadjuvant chemotherapy (NACT) was initially applied to locally advanced breast cancer to convert advanced lesions to an operable status. Currently, its application has been expanded to enhance ...overall oncological results, especially in patients with triple-negative or HER-2-positive breast cancer. With more NACT being applied, the role and impact of this approach on breast reconstruction needs to be determined. This study aimed to perform a complete reconstructive outcome analysis of patients receiving NACT who underwent immediate breast reconstruction.
A retrospective review of a single reconstructive surgeon's immediate breast reconstructions performed from July 2008 to December 2018 was undertaken. The results were stratified by the use of NACT. Patient demographics, delivery of NACT, adjuvant treatment, incidence of surgical complications, and postoperative photographs were analyzed.
A total of 269 patients were included. The mean follow-up was 46.3 months. Forty-six out of 269 patients received NACT and were included in the NACT group. The other patients were included in the non-NACT group. When implant-based reconstruction was planned, the NACT group had a higher rate of two-stage tissue expander-implant reconstruction than direct-to-implant reconstruction (p < 0.001). The requirement for postmastectomy radiotherapy was higher in the NACT group (p < 0.001). The surgical complication rates were similar between groups after adjusting for confounding factors. The objective aesthetic outcomes assessed by 6 plastic surgeons were also similar between groups.
Immediate breast reconstruction is a safe and reliable procedure, with an acceptable reconstructive complication rate and satisfactory aesthetic outcomes, for patients treated with NACT.
Background
The deep inferior epigastric artery perforator (DIEP) flap is widely used in breast reconstruction and the profunda artery perforator (PAP) flap as alternative. However, the difference ...between the two flaps in smaller breast reconstruction remains lacking, in particular, the donor site complications. In this case series, the results of small breast reconstruction (≤300 g) using PAP or small DIEP flaps were explored.
Methods
Unilateral immediate breast reconstruction using a free PAP flap or small DIEP flap (≤300 g) from 2011 to 2021 were reviewed retrospectively. Excluding patients with delayed reconstruction, 28 patients, including 17 PAP flaps and 11 small DIEP flaps were enrolled. Flap characteristics, breast and donor site complications, and revision surgeries were reviewed. BREAST‐Q™ was used for quality‐of‐life assessment.
Results
Compared with a small DIEP flap, a PAP flap was narrow (7.5 ± 1.1 vs. 10.6 ± 0.7 cm, p < .001), short (20.0 ± 2.6 vs. 25.5 ± 1.8 cm, p < .001) and had a shorter pedicle (5.9 ± 1.6 vs. 9.1 ± 1.0 cm, p < .001). There were no significant differences in acute and late complications of wound healing and fat necrosis, but the average number of revisions in the PAP group was significantly higher (1.9 ± 1.3 vs. 0.8 ± 1.4, p = .041). Patient‐reported outcomes using BREAST‐Q™ displayed no significant difference between the two groups.
Conclusion
The outcomes of PAP and small DIEP flaps at the breasts and donor sites are satisfactory, despite that a higher tendency of donor site complications in PAP flap and more aesthetic refinement required in the PAP group. The overall outcomes are acceptable.
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