INT192450

Context Info Confidence 0.55 First Reported 2006 Last Reported 2011 Negated 2 Speculated 0 Reported most in Body Documents 26 Total Number 50 Disease Relevance 18.82 Pain Relevance 3.26

cytosol (CLTC) mitosis (CLTC) mitochondrion (CLTC) vesicle-mediated transport (CLTC) structural molecule activity (CLTC) plasma membrane (CLTC)

Anatomy Link Frequency cortex 3 neurons 2 astrocytes 2 primary visual cortex 2 SWM 2 CLTC (Homo sapiens)

Pain Link Frequency Relevance Heat Neuropathic pain 156 99.80 intrathecal 32 98.92 cva 85 98.44 Pain 375 94.16 lidocaine 32 91.80 ischemia 32 87.56 reflex sympathetic dystrophy 35 85.72 fifth nerve 39 85.16 Rsd 32 80.60 imagery 54 77.16

Disease Link Frequency Relevance Heat Infection 352 100.00 Neuropathic Pain 210 99.80 Disease 1953 99.76 Targeted Disruption 41 99.56 Toxicity 41 99.46 Penile Induration 176 99.12 Urological Neuroanatomy 30 99.12 Recurrence 320 98.88 Hemorrhage 126 98.44 Keloid Scars 176 98.36

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To further validate the findings obtained from the initial screen, we have selected these genes (CLTC, AP2B1, DNM2, ARRB1, ATP6V0A1 & ARPC1B) for re-confirming their inhibitory effects on DENV infection.

Gene_expression (infection) of CLTC associated with infection

1) Confidence 0.55 Published 2010 Journal Virol J Section Body Doc Link PMC2825209 Disease Relevance 0.54 Pain Relevance 0

To determine whether the different serotypes of DENV (DENV 1 to 4) utilized clathrin-mediated endocytosis to gain entry into Huh7 cells, cells were reverse-transfected with different concentration of siRNAs that target clathrin heavy chain (CLTC) and subjected to DENV 1 to 4 infection (MOI of 1).

Gene_expression (target) of clathrin heavy chain associated with infection

2) Confidence 0.55 Published 2010 Journal Virol J Section Body Doc Link PMC2825209 Disease Relevance 0.43 Pain Relevance 0.04

85.8% of those receiving a single injection developed anti-CHC antibodies, with 100% of patients testing positive following three injections.

Gene_expression (antibodies) of anti-CHC

3) Confidence 0.49 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 1.13 Pain Relevance 0.37

85.8% of those receiving a single in vivo CHC injection into DD-affected cords developed anti-CHC antibodies, with 100% of patients testing positive following three injections.

Gene_expression (antibodies) of anti-CHC associated with disease

4) Confidence 0.49 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.48 Pain Relevance 0

To determine whether the different serotypes of DENV (DENV 1 to 4) utilized clathrin-mediated endocytosis to gain entry into Huh7 cells, cells were reverse-transfected with different concentration of siRNAs that target clathrin heavy chain (CLTC) and subjected to DENV 1 to 4 infection (MOI of 1).

Gene_expression (target) of CLTC associated with infection

5) Confidence 0.48 Published 2010 Journal Virol J Section Body Doc Link PMC2825209 Disease Relevance 0.48 Pain Relevance 0.04

The knock-down of ATP6V0A1 and CLTC (at concentration of 50 nM) produced the strongest inhibition of DENV infection. siRNA smart pool-based deconvolution assays targeting CLTC, AP2B1, DNM2, ARRB1, ATP6V0A1 and ARPC1B were also performed to ensure that inhibitory effects on DENV infection observed in the primary screen was specific and not due to off-target gene effects of the siRNA primary screen. 30 nM of each specific individual siRNA of the smart pool (4 specific siRNAs) directed against each of the respective genes were reverse transfected into RD cells and subsequently subjected to DENV infection.

Gene_expression (produced) of CLTC associated with targeted disruption and infection

6) Confidence 0.43 Published 2010 Journal Virol J Section Body Doc Link PMC2825209 Disease Relevance 0.74 Pain Relevance 0

All patients had a single CHC injection, six into MCPJ and two into PIPJ; however, varying injection dosages were administered, and not all patients achieved the primary goal of extension to ?

Gene_expression (injection) of CHC

7) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.99 Pain Relevance 0.05

Of these 23, only eight were alive, contactable at the same address, available within the study period and received a CHC injection and thus were eligible for reevaluation to assess the state of their DD since the study.

Gene_expression (injection) of CHC associated with disease

8) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.90 Pain Relevance 0.06

These papers have investigated safe and efficacious doses for the injection of CHC to treat palpable DD cords in adult patients and have shown significant short- to mid-term results for correction to near-full digital extension (?

Gene_expression (injection) of CHC associated with disease

9) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Abstract Doc Link PMC2988615 Disease Relevance 1.34 Pain Relevance 0

CHC produced no alteration in volume in the injected hypertrophic scars.

Neg (no) Gene_expression (produced) of CHC associated with keloid scars

10) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 1.26 Pain Relevance 0.16

Overall, the authors concluded CHC injection to be safe, effective, and less-invasive treatment option for the management of DD contractures.

Gene_expression (injection) of CHC associated with contracture and disease

11) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.87 Pain Relevance 0.09

The toxicity of intravenously injected CHC in mice was explored by Garvin Jr86 who showed a median lethal dose of 1,176 ± 208 U/kg – the main signs of toxicity were pulmonary hemorrhage and disseminated tissue digestion.

Gene_expression (explored) of CHC associated with toxicity and cva

12) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.72 Pain Relevance 0.16

In view of this requirement for meticulous technique, it is clear that CHC injection will remain, based on the need for sound anatomical knowledge and manual dexterity, within the surgeons’ remit.

Gene_expression (injection) of CHC

13) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.98 Pain Relevance 0.23

In another study, they showed that CHC injected epidurally resulted in local dural thinning at higher concentrations, whereas even small concentrations of CHC injected intrathecally resulted in intrathecal hemorrhage and acute paraplegia.

Gene_expression (injected) of CHC associated with paraplegia, cva and intrathecal

14) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.52 Pain Relevance 0.20

This allowed extrapolation that a CHC injection of 300 U was the minimum potential dose for in vivo clinical use that would result in DD cord rupture (and hence correction of the fixed flexion deformity) following normal active digital extension.

Gene_expression (injection) of CHC associated with rupture and disease

15) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 1.28 Pain Relevance 0

85.8% of those receiving a single in vivo CHC injection into DD-affected cords developed anti-CHC antibodies, with 100% of patients testing positive following three injections.

Gene_expression (injection) of CHC associated with disease

16) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.42 Pain Relevance 0

Despite this lack of cellular sequelae, the manufacturers of the CHC Xiaflex® advise that CHC injection has not been tested in pregnant, breast-feeding, or pediatric populations in whom its safety and efficacy have not yet been established.

Gene_expression (injection) of CHC

17) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.65 Pain Relevance 0.15

Surgery is, however, likely to remain a valid treatment option, especially for recurrent cases following CHC injection, in patients with the aggressive form of the disease (strong diathesis), and in those patients with PIPJ involvement (which appears to not respond as favorably to the CHC-based technique when compared with simple MCPJ disease).

Gene_expression (injection) of CHC associated with disease susceptibility and disease

18) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.78 Pain Relevance 0

Indeed, Hamilton et al74 demonstrated such an immune response to injection of CHC for the treatment of PD plaques: pretreatment, anticollagenase IgG was detected in 34% of the healthy controls vs 58% of untreated PD patients.

Gene_expression (injection) of CHC in plaques associated with penile induration

19) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.26 Pain Relevance 0

Adverse effects of CHC injection were the same as detailed in the authors’ previous paper, remaining locally confined and well tolerated, with the addition of three superficial skin tears secondary to rapid stretching of the overlying skin during cord rupture.

Gene_expression (injection) of CHC in skin associated with rupture

20) Confidence 0.42 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2988615 Disease Relevance 0.74 Pain Relevance 0

General Comments

This test has worked.