TNF-α: the shape of small molecules to come?

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing pandemic coronavirus disease 2019 (COVID-19). The majority of patients with COVID-19 have a good prognosis, but variable percentages in different countries develop pneumonia associated with lymphocytopenia and severe inflammatory response due to uncontrolled release of cytokines. These immune mediators are transcriptionally regulated by JAK-STAT molecular pathways, which can be disabled by small molecules. Here, we provide evidences on the efficacy of baricitinib, a JAK1/JAK2 inhibitor, in correcting the immune abnormalities observed in patients hospitalized with COVID-19. Indeed, we demonstrate a significant reduction in serum levels of interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)α, a rapid recovery in circulating T and B cell frequencies and an increased antibody production against SARS-CoV-2 spike protein in baricitinib-treated patients. Moreover, treated patients underwent a rapid reduction in oxygen flow need and progressive increase in the P/F. Our work provides the basis on developing effective treatments against COVID-19 pathogenesis using on-target therapy.

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Efficacy of biological therapies and small molecules in moderate to severe ulcerative colitis: systematic review and network meta-analysis

Gut ◽

10.1136/gutjnl-2021-326390 ◽

2021 ◽

pp. gutjnl-2021-326390

Author(s):

Nicholas E Burr ◽

David J Gracie ◽

Christopher J Black ◽

Alexander C Ford

Keyword(s):

Ulcerative Colitis ◽

Adverse Events ◽

Small Molecules ◽

Clinical Remission ◽

Meta Analysis ◽

Biological Therapies ◽

Serious Adverse Events ◽

Once Daily ◽

Tnf Α ◽

Reported Data

ObjectiveBiological therapies and small molecules continue to be evaluated in moderate to severely active ulcerative colitis, but are often studied in placebo-controlled trials, meaning their relative efficacy and safety is unknown. We examined this in a network meta-analysis.DesignWe searched the literature to October 2021 to identify eligible trials. We judged efficacy using clinical remission, endoscopic improvement, or clinical response, and according to previous exposure or non-exposure to antitumour necrosis factor (TNF)-α therapy. We also assessed safety. We used a random effects model and reported data as pooled relative risks (RRs) with 95% CIs. Interventions were ranked according to their P-score.ResultsWe identified 28 trials (12 504 patients). Based on failure to achieve clinical remission, upadacitinib 45 mg once daily ranked first versus placebo (RR 0.73; 95% CI 0.68 to 0.80, P-score 0.98), with infliximab 5 mg/kg and 10 mg/kg second and third, respectively. Upadacitinib ranked first for clinical remission in both patients naïve to anti-TNF-α drugs (RR 0.69; 95% CI 0.61 to 0.78, P-score 0.99) and previously exposed (RR 0.78; 95% CI 0.72 to 0.85, P-score 0.99). Upadacitinib was superior to almost all other drugs in these analyses. Based on failure to achieve endoscopic improvement infliximab 10 mg/kg ranked first (RR 0.61; 95% CI 0.51 to 0.72, P-score 0.97), with upadacitinib 45 mg once daily, second, and infliximab 5 mg/kg third. Upadacitinib was more likely to lead to adverse events, but serious adverse events were no more frequent, and withdrawals due to adverse events were significantly lower than with placebo. Infections were significantly more likely with tofacitinib than placebo (RR 1.41; 95% CI 1.03 to 1.91).ConclusionIn a network meta-analysis, upadacitinib 45 mg once daily ranked first for clinical remission in all patients, patients naïve to anti-TNF-α drugs and patients previously exposed. Infliximab 10 mg/kg ranked first for endoscopic improvement. Most drugs were safe and well tolerated.

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Perkembangan Terkini Terapi Sistemik Psoriasis

Jurnal Kedokteran Meditek ◽

10.36452/jkdoktmeditek.v27i2.2043 ◽

2021 ◽

Vol 27 (2) ◽

pp. 136-146

Author(s):

Natalia Rania Sutanto ◽

Windy Keumala Budianti

Keyword(s):

Small Molecules ◽

Tnf Α

Psoriasis merupakan penyakit inflamasi kulit akibat aktivasi terhadap sistem imun bawaan dan adaptif. Etiopatogenesis psoriasis merupakan proses kompleks dan multifaktorial, yang dipengaruhi oleh faktor genetik dan lingkungan seperti stres, trauma, dan infeksi. Pada pasien dengan psoriasis kategori sedang hingga berat dan lesi lokalisata di area skalp, wajah, kuku, telapak tangan dan kaki, serta genital merupakan indikasi untuk pemberian terapi dengan obat sistemik. Saat ini terdapat berbagai pilihan terapi sistemik yang tersedia yaitu obat sistemik konvensional, terapi small molecules, obat biologik, dan biosimilarnya yang terdiri atas inhibitor TNF-α, inhibitor IL-12/23, inhibitor IL-17, dan inhibitor IL-23. Selama dekade terakhir, tata laksana psoriasis telah mengalami pergeseran paradigma yaitu obat biologik dan biosimilarnya mulai menjadi pilihan utama karena telah terbukti memiliki efektivitas baik, dengan efek samping minimal. Tinjauan pustaka ini membahas perkembangan terapi sistemik psoriasis terkini sehingga diharapkan dapat memberikan acuan untuk memilih terapi yang tepat, efektif, dan aman untuk pasien psoriasis.

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Investor-State Dispute Settlement under NAFTA Chapter 11: The Shape of Things to Come?

Canadian Yearbook of international Law/Annuaire canadien de droit international ◽

10.1017/s0069005800006652 ◽

1998 ◽

Vol 35 ◽

pp. 263-290

Author(s):

J. Anthony VanDuzer

Keyword(s):

Free Trade Agreement ◽

Dispute Settlement ◽

Trade Agreement ◽

Minimum Standards ◽

The North ◽

State Behaviour ◽

Nafta Chapter 11 ◽

To Come ◽

The Right

SummaryRecently, there has been a proliferation of international agreements imposing minimum standards on states in respect of their treatment of foreign investors and allowing investors to initiate dispute settlement proceedings where a state violates these standards. Of greatest significance to Canada is Chapter 11 of the North American Free Trade Agreement, which provides both standards for state behaviour and the right to initiate binding arbitration. Since 1996, four cases have been brought under Chapter 11. This note describes the Chapter 11 process and suggests some of the issues that may arise as it is increasingly resorted to by investors.

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Scanning Electron Microscopy-cuticular Lesions on the Roundworm Ascaris Suum

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010006756x ◽

1970 ◽

Vol 28 ◽

pp. 114-115

Author(s):

P. A. Madden ◽

W. R. Anderson

Keyword(s):

Electron Microscopy ◽

Scanning Electron Microscopy ◽

Freeze Drying ◽

Room Temperature ◽

Secondary Electron ◽

Distilled Water ◽

Freeze Dried ◽

Silver Paint ◽

To Come ◽

Scanning Electron

The intestinal roundworm of swine is pinkish in color and about the diameter of a lead pencil. Adult worms, taken from parasitized swine, frequently were observed with macroscopic lesions on their cuticule. Those possessing such lesions were rinsed in distilled water, and cylindrical segments of the affected areas were removed. Some of the segments were fixed in buffered formalin before freeze-drying; others were freeze-dried immediately. Initially, specimens were quenched in liquid freon followed by immersion in liquid nitrogen. They were then placed in ampuoles in a freezer at −45C and sublimated by vacuum until dry. After the specimens appeared dry, the freezer was allowed to come to room temperature slowly while the vacuum was maintained. The dried specimens were attached to metal pegs with conductive silver paint and placed in a vacuum evaporator on a rotating tilting stage. They were then coated by evaporating an alloy of 20% palladium and 80% gold to a thickness of approximately 300 A°. The specimens were examined by secondary electron emmission in a scanning electron microscope.

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Gap junctions in the prothoracic glands of the tobacco hornworm, Manduca sexta

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100123933 ◽

1992 ◽

Vol 50 (1) ◽

pp. 706-707

Author(s):

Ji-da Dai ◽

M. Joseph Costello ◽

Lawrence I. Gilbert

Keyword(s):

Gap Junctions ◽

Small Molecules ◽

Manduca Sexta ◽

Freeze Fracture ◽

Cell Communication ◽

Cellular Level ◽

Thin Sections ◽

Prothoracic Glands ◽

Polyhydroxylated Steroids ◽

Stimulation Of

Insect molting and metamorphosis are elicited by a class of polyhydroxylated steroids, ecdysteroids, that originate in the prothoracic glands (PGs). Prothoracicotropic hormone stimulation of steroidogenesis by the PGs at the cellular level involves both calcium and cAMP. Cell-to-cell communication mediated by gap junctions may play a key role in regulating signal transduction by controlling the transmission of small molecules and ions between adjacent cells. This is the first report of gap junctions in the PGs, the evidence obtained by means of SEM, thin sections and freeze-fracture replicas.

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The microstructure change of low-carbon electrical steels by residual aluminum

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100153403 ◽

1989 ◽

Vol 47 ◽

pp. 286-287

Author(s):

C.K. Hou ◽

C.T. Hu ◽

Sanboh Lee

Keyword(s):

Annealing Treatment ◽

Low Carbon ◽

Electrical Steels ◽

Vacuum Degassing ◽

Spherical Inclusions ◽

Residual Aluminum ◽

Average Grain Size ◽

The Matrix ◽

Fine Size ◽

To Come

The fully processed low-carbon electrical steels are generally fabricated through vacuum degassing to reduce the carbon level and to avoid the need for any further decarburization annealing treatment. This investigation was conducted on eighteen heats of such steels with aluminum content ranging from 0.001% to 0.011% which was believed to come from the addition of ferroalloys.The sizes of all the observed grains are less than 24 μm, and gradually decrease as the content of aluminum is increased from 0.001% to 0.007%. For steels with residual aluminum greater than 0. 007%, the average grain size becomes constant and is about 8.8 μm as shown in Fig. 1. When the aluminum is increased, the observed grains are changed from the uniformly coarse and equiaxial shape to the fine size in the region near surfaces and the elongated shape in the central region. SEM and EDAX analysis of large spherical inclusions in the matrix indicate that silicate is the majority compound when the aluminum propotion is less than 0.003%, then the content of aluminum in compound inclusion increases with that in steel.

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Fusion and Fission Processes in Exocytosis: Possible Roles for Synexin and Osmotic Lysis in the Two Events

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s1431927600002634 ◽

1980 ◽

Vol 38 ◽

pp. 594-597

Author(s):

H.B. Pollard ◽

C.E. Creutz ◽

C.J. Pazoles ◽

J.H. Scott

Keyword(s):

Small Molecules ◽

Chromaffin Cells ◽

Adrenal Glands ◽

General Concept ◽

Extracellular Calcium ◽

Large Protein ◽

Granule Membrane ◽

Osmotic Lysis ◽

Per Se ◽

Chemical Evidence

Exocytosis is a general concept describing secretion of enzymes, hormones and transmitters that are otherwise sequestered in intracellular granules. Chemical evidence for this concept was first gathered from studies on chromaffin cells in perfused adrenal glands, in which it was found that granule contents, including both large protein and small molecules such as adrenaline and ATP, were released together while the granule membrane was retained in the cell. A number of exhaustive reviews of this early work have been published and are summarized in Reference 1. The critical experiments demonstrating the importance of extracellular calcium for exocytosis per se were also first performed in this system (2,3), further indicating the substantial service given by chromaffin cells to those interested in secretory phenomena over the years.

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