Expert opinion on thyroid complications of new anti-cancer therapies: Tyrosine kinase inhibitors

Thyroid pathology is the most frequent form of endocrinopathy during tyrosine kinase inhibitor (TKI) treatment. Dysthyroidism occurs in 10% to 80% of cases, depending on diagnostic criteria. In patients with intact thyroid gland prior to TKI treatment, incidence of dysthyroidism is 30–40%, with subclinical presentation in half of cases. It mainly involves hypothyroidism, preceded in 20–40% of cases by transient thyrotoxicosis that may go overlooked. The pathophysiological mechanism is “vascular” thyroiditis induced by the anti-angiogenic action of TKIs. Between 20% and 60% of patients receiving levothyroxine ahead of TKI treatment show increased levothyroxine requirements. TKIs should not be discontinued because of onset of thyroid dysfunction. Treatment is symptomatic in case of thyrotoxicosis, and levothyroxine replacement therapy is initiated in case of symptomatic hypothyroidism or TSH > 10 mIU/L. During TKI treatment, TSH should be assayed monthly, or at end of off-period (i.e., day 1 of new cycle after interruption), for the first 6 months, then every 2–3 months or in case of clinical signs of dysthyroidism. In patients already treated for hypothyroidism, TSH should be assayed monthly for 3 months, then every 3 months throughout treatment. At TKI termination, remission of hypothyroidism is possible but unpredictable, and progressive discontinuation of levothyroxine may be considered under monitoring. Teamwork between oncologists and endocrinologists improves screening and treatment of thyroid dysfunction, enabling the patient to be better accompanied during treatment.     

KDM6B epigenetically regulated-interleukin-6 expression in the dorsal root ganglia and spinal dorsal horn contributes to the development and maintenance of neuropathic pain following peripheral nerve injury in male rats

The lysine specific demethylase 6B (KDM6B) has been implicated as a coregulator in the expression of proinflammatory mediators, and in the pathogenesis of inflammatory and arthritic pain. However, the role of KDM6B in neuropathic pain has yet to be studied. In the current study, the neuropathic pain was determined by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) following lumbar 5 spinal nerve ligation (SNL) in male rats. Immunohistochemistry, Western blotting, qRT-PCR, and chromatin immunoprecipitation (ChIP)-PCR assays were performed to investigate the underlying mechanisms. Our results showed that SNL led to a significant increase in KDM6B mRNA and protein in the ipsilateral L4/5 dorsal root ganglia (DRG) and spinal dorsal horn; and this increase correlated a markedly reduction in the level of H3K27me3 methylation in the same tissue. Double immunofluorescence staining revealed that the KDM6B expressed in myelinated A- and unmyelinated C-fibers in the DRG; and located in neuronal cells, astrocytes, and microglia in the dorsal horn. Behavioral data showed that SNL-induced mechanical allodynia and thermal hyperalgesia were impaired by the treatment of prior to i.t. injection of GSK-J4, a specific inhibitor of KDM6B, or KDM6B siRNA. Both microinjection of AAV2-EGFP-KDM6B shRNA in the lumbar 5 dorsal horn and sciatic nerve, separately, alleviated the neuropathic pain following SNL. The established neuropathic pain was also partially attenuated by repeat i.t. injections of GSK-J4 or KDM6B siRNA, started on day 7 after SNL. SNL also resulted in a remarkable increased expression of interleukin-6 (IL-6) in the DRG and dorsal horn. But this increase was dramatically inhibited by i.t. injection of GSK-J4 and KDM6B siRNA; and suppressed by prior to microinjection of AAV2-EGFP-KDM6B shRNA in the dorsal horn and sciatic nerve. Results of ChIP-PCR assay showed that SNL-induced enhanced binding of STAT3 with IL-6 promoter was inhibited by prior to i.t. injection of GSK-J4. Meanwhile, the level of H3K27me3 methylation was also decreased by the treatment. Together, our results indicate that SNL-induced upregulation of KDM6B via demethylating H3K27me3 facilitates the binding of STAT3 with IL-6 promoter, and subsequently mediated-increase in the expression of IL-6 in the DRG and dorsal horn contributes to the development and maintenance of neuropathic pain. Targeting KDM6B might a promising therapeutic strategy to treatment of chronic pain.     

Characteristics of pediatric invasive pneumococcal diseases and the pneumococcal isolates in Suzhou,China before introduction of PCV13

BackgroundData on characteristics of invasive pneumococcal diseases (IPD) is limited in China. We aimed to understand the clinical features and explore the molecular characteristics of the pneumococcal isolates in China.MethodsSince 2010, we prospectively collected the pneumococcal isolates and the IPD patients’ demographic and clinical information in Suzhou University Affiliated Children’s Hospital (SCH). The antibiotic susceptibility, serotypes, genotypes of Streptococcus pneumoniae strains were identified by E-test, quellung reaction and/or multiplex PCR, and multi-locus sequence typing, respectively.ResultsDuring the period from January 2010 to December 2015, a total of 80 IPD patients were identified. They were diagnosed as meningitis (31.3%), septicemia (27.5%), pneumonia (21.3%) and others (20.0%). About half of them required vancomycin treatment, 42.5% were admitted to ICUs, 36.2% had complications and 6.2% were hospitalized for over 1 year. The most common serotypes of the pneumococcal isolates were serotypes 6B and 14, the coverage of PCV13 was 92.5%, and CC236s and CC199s were the most common clone complexes.ConclusionsPediatric IPD patients had severe clinical symptoms, demanded intensive treatment, suffered poor prognosis and substantial burden. The pneumococcal isolates’ serotype coverage of PCV13 vaccine was high, which leads to implication of PCV vaccine usage among children in China.     

Differential ligand regulation of PlexB signaling in motor neuron axon guidance in Drosophila

Plexins (Plexs) are a large family of phylogenetically conserved guidance receptors that bind specifically to semaphorins (Semas), another large family of guidance molecules. In the Drosophila embryonic central nervous system (CNS), the secreted semaphorins Sema-2a and Sema-2b both act as ligands for PlexB, but mediate mutually independent and opposite functions (repulsive and attractive guidance, respectively). PlexB is also known to regulate motor axon guidance in the embryonic peripheral nervous system (PNS). However, it is unclear whether the mechanisms of ligand regulation of PlexB seen in the CNS are similar or the same as those that exist in PNS motor axon guidance. Here, we find that two distinct modes of ligand regulation underlie differential roles of PlexB in PNS motor axon pathfinding during embryonic development. Epistasis analyses in the intersegmental nerve b (ISNb) pathway suggest that PlexB serves as a receptor for both Sema-2a and Sema-2b and integrates their mutually dependent but opposite guidance functions. Furthermore, we present evidence that PlexB mediates not only Sema-2a/2b-dependent guidance functions, but also Sema-2a/2b-independent target recognition in establishing the segmental nerve a (SNa) motor axon pathway. These results demonstrate that a single guidance receptor can elicit diverse effects on the establishment of neuronal connectivity via regulation of its ligands themselves.     

Methods for development of a core outcome set for clinical trials integrating traditional Chinese medicine and Western medicine

Clinical trial outcome reporting differs between studies integrating traditional Chinese medicine (TCM) and Western medicine, so that some clinical trials are not eligible for inclusion in a systematic review. The excluded studies are therefore less widely disseminated, and even valid studies are less likely to yield impact. This problem may be addressed by developing core outcome sets (COSs) for integrative medicine in specific healthcare areas. The first stage of development is to define the scope of the COS for integrative medicine, the second stage is to establish the need for such a COS, and the third stage is to develop a protocol and register the COS. The final stage involves three steps: (i) development of a comprehensive list of outcomes (including efficacy outcomes and safety outcomes and TCM syndromes) using systematic review, qualitative or cross-sectional research, and reviews of package inserts and medical records; (ii) merging and grouping of outcomes within domains; (iii) conducting two rounds of Delphi survey and consensus meetings with a range of stakeholders. The final COS will include a general COS and core TCM syndrome- set. Development of COSs for clinical trials of integrative medicine may help to standardize outcome reporting and reduce publication bias in the future.