Tocilizumab Exerts Anti-Tumor Effects on Colorectal Carcinoma Cell Xenografts Corresponding to Expression Levels of Interleukin-6 Receptor.

The use of tocilizumab against the interleukin-6 receptor (IL-6R) has been demonstrated as inhibiting the progression of diverse cancers in vitro and in vivo. Nonetheless, evidence regarding the anti-tumor effects of tocilizumab on human colorectal carcinoma (CRC) corresponding to IL-6R expression levels remains scarce. To investigate the influence of IL-6R expression, SW480 and HT-29 cells inoculated subcutaneously into NU/NU mice were used as human CRC xenograft models with anti-IL-6R antibody (tocilizumab) therapy. The IL-6R expression levels, histology of CRC growth/invasiveness, and tumor growth-related signaling pathway were estimated by H&E and immunohistochemical staining. SW480 tumor cells with higher IL-6R expression levels showed better responsiveness in tocilizumab therapy than in the treated HT-29 group. Likewise, therapeutic effects of tocilizumab on the proliferative ability with mitotic index and Ki-67 expressions, invasiveness with MMP-9 proteinase expressions, and ERK 1/2 and STAT3 signaling transduction in the SW480 treatment group were superior to the HT-29 treatment group. In light of our results, IL-6R is the key indicator for the efficacy of tocilizumab treatment in CRC xenografts. From the perspective of precision medicine, tumor response to anti-IL-6R antibody therapy could be predicted on the basis of IL-6R expression levels. In this manner, tocilizumab may serve as a targeted and promising anti-CRC therapy.

Addition of adipose tissue-derived mesenchymal stem cells improves empagliflozin therapy for alleviating hyperglycemia--induced neuropathy.

BACKGROUND: We examined the impact of adipose-derived mesenchymal stem cell (ADMSC)-facilitated empagliflozin (EMPA) therapy for alleviating hyperglycemic induced neuropathy [i.e., diabetic neuropathy (DN)]. METHODS: Study constituted N2a cell culture and rats to be classified into groups 1 (sham-operated-control)/2 (DN)/3 (DN + empagliflozin/20 mg/kg/daily orally for 6 weeks since post-day-7 DN induction)/4 (DN + ADMSCs/1.2 × 106 cells by vein transfusion at time intervals of 1/3/5 weeks after DN induction)/5 (DN + empagliflozin + ADMSCs) and sacrificed by day-42 after DN induction. RESULTS: In vitro results showed that, compared to N2a cells, the cellular levels of senescence/DNA-damage and protein expressions of oxidative-stress (OS), apoptotic, autophagic and inflammatory biomarkers were significantly higher in N2a + glucose (25 mM) but were significantly reversed in N2a + glucose + ADMSCs, whereas the cellular levels of mitochondrial cytochrome C and protein levels of anti-oxidants displayed an opposite pattern of OS (all P<0.001). The above-mentioned parameters (i.e., OS/apoptosis/fibrosis/autophagy/DNA-damage) were lowest in N2a cells, highest in N2a + glucose and significantly higher in N2a + glucose + EMPA (50 µM) than in N2a + glucose + EMPA (150 µM) (all P<0.001). By days 7/14/21/28/35/42 after DN induction, the values of thermal paw-withdrawal-latency (TPWL)/mechanical-paw-withdrawal-threshold were highest in group 1 and significantly progressively increased from groups 2/4/3/5 (all P<0.0001). The cellular levels of unmyelinated C- and myelinated A-δ fibers, and protein levels of OS/apoptotic/DNA-damaged/fibrotic/autophagic/inflammatory/pain-facilitated/voltage-gated sodium channel biomarkers in L4-L5 levels of dorsal-root-ganglia exhibited an contradictory manner of TPWL among the groups (all P<0.0001). CONCLUSIONS: Combination of EMPA and ADMSC therapy was superior to either alone for improving outcomes of DN.

New records of the squat lobster genus Munidopsis Whiteaves, 1874 (Crustacea, Decapoda, Munidopsidae) from the deep sea off Taiwan.

Two species of the squat lobster family Munidopsidae, Munidopsisalbatrossae Pequegnat & Pequegnat, 1973 and M.pycnopoda Baba, 2005, are reported from Taiwan for the first time based on specimens collected from lower bathyal depths. The Taiwanese material of M.pycnopoda also represents the first record of the species from the Pacific Ocean and greatly extends this species' geographical range from the western Indian Ocean to western Pacific. The giant Munidopsis specimen from Taiwan is identified as M.albatrossae mainly by DNA barcoding even though M.albatrossae and M.aries (A. Milne-Edwards, 1880) are both morphologically and genetically extremely similar.

Finding the Missing Puzzle Piece of the Nisto Stage in the Larval Cycle of the Slipper Lobster Scyllarides squammosus: A Molecular and Morphological Approach.

Slipper and spiny lobsters are crustaceans that are in high demand and possess great commercial potential as valuable foods. The early life stages are important to understand the distribution and resource ecology of those lobsters. However, much less information is available about slipper lobsters than spiny lobsters. Biological information concerning the transition stage from the planktonic to the benthic phase, the so-called nisto stage, is limited probably due to its short duration. An individual scyllarid nisto was discovered while scuba diving off Chichijima Island. DNA analyses using mitochondrial 16S rRNA and cytochrome c oxidase subunit 1 (COI) genes confirmed this specimen to be Scyllarides squammosus (H. Milne Edwards, 1837). Detailed morphological observations of this specimen and its comparison with previous reports on Scyllarides nistos suggest that the diagnostic character of S. squammosus nisto is the pleura of the second to fifth pleonites possessing prominent teeth entirely on the lateral margin. Other morphological characteristics are the carapace with the widest distance in the middle and the second to fifth pleonites bearing two tubercles on each side. This report describes the identification of the first worldwide record of a Scyllarides nisto, confirmed by molecular barcoding.

On two new species of deep-sea carrier crabs (Crustacea, Brachyura, Homolodromiidae, Dicranodromia) from Taiwan and the Philippines, with notes on other Indo-West Pacific species.

The systematics of four species of the homolodromiid genus Dicranodromia A. Milne-Edwards, 1880, from East Asia and the Philippines is reappraised: D.danielae Ng & McLay, 2005, D.doederleini Ortmann, 1892, D.karubar Guinot, 1993, and D.martini Guinot, 1995; and key characters such as the epistome, gonopods, and spermatheca are figured in detail. Two new species, D.erinaceus sp. nov. and D.robusta sp. nov., are described from Taiwan and the Philippines, respectively. Dicranodromiaerinaceus sp. nov. resembles D.spinulata Guinot, 1995, and D.delli Ahyong, 2008 (from New Caledonia and New Zealand) but can be separated by its distinctly spinulated carapace surfaces and proportionately shorter fifth ambulatory legs. Dicranodromiarobusta sp. nov. is superficially similar to D.baffini (Alcock & Anderson, 1899) and D.karubar Guinot, 1993, but can easily be separated by possessing a broad dorsoventrally flattened infraorbital tooth. A genetic study of the species using the mitochondrial cytochrome c oxidase I gene confirms that the taxa are distinct, with D.erinaceus sp. nov. coming out in a well-supported clade from congeners. The megalopa of D.doederleini is also reported for the first time.

Antibody to Interleukin-6 Receptor Inhibits In Vivo Growth of Human Colorectal Carcinoma Cell Xenografts.

BACKGROUND: Interleukin-6 receptor antibody (IL6R) inhibits colony formation and invasion by colorectal carcinoma (CRC) in vitro. We examined the effect of IL6R antibody on tumor growth of CRC xenografts in vivo. MATERIALS AND METHODS: SW480 cells inoculated subcutaneously into NU/NU mice were treated with anti-IL6R and tumor histology and growth-related signaling were subsequently estimated by hematoxylin and eosin and immunohistochemical staining. RESULTS: Tumor growth was inhibited by anti-IL6R treatment at dosages of both 0.1 and 1.0 mg/kg. Tumor cells had invaded into surrounding tissues in untreated mice, while there was no invasion of tumors in the IL6R antibody-treated mice. The expression of Ki-67, signal transducer and activator of transcription protein 3 (STAT3) and phosphor-extracellular signal-regulated kinase 1 and 2 (ERK1/2) were suppressed in anti-IL6R-treated tumors. CONCLUSION: IL6R antibody inhibited tumor growth and invasiveness in vivo by suppressing the expression of Ki-67, STAT3 and phosphor-ERK1/2. The results imply that the anti-IL6R may be a promising targeted drug for CRC.

Gut Microbiota in Decapod Shrimps: Evidence of Phylosymbiosis.

Gut microbiota have long attracted the interest of scientists due to their profound impact on the well-being of animals. A non-random pattern of microbial assembly that results in a parallelism between host phylogeny and microbial similarity is described as phylosymbiosis. Phylosymbiosis has been consistently observed in different clades of animal hosts, but there have been no studies on crustaceans. In this study, we investigated whether host phylogeny has an impact on the gut microbiota assemblages in decapod shrimps. We examined the gut microbial communities in 20 shrimp species from three families inhabiting distinct environments, using metabarcoding analyses of the V1-V3 hypervariable region of the 16S rRNA gene. Gut microbial communities varied within each shrimp group but were generally dominated by Proteobacteria. A prevalent phylosymbiotic pattern in shrimps was evidenced for the first time by the observations of (1) the distinguishability of microbial communities among species within each group, (2) a significantly lower intraspecific than interspecific gut microbial beta diversity across shrimp groups, (3) topological congruence between host phylogenetic trees and gut microbiota dendrograms, and (4) a correlation between host genetic distances and microbial dissimilarities. Consistent signals of phylosymbiosis were observed across all groups in dendrograms based on the unweighted UniFrac distances at 99% operational taxonomic units (OTUs) level and in Mantel tests based on the weighted UniFrac distances based on 97% OTUs and amplicon sequence variants. Penaeids exhibited phylosymbiosis in most tests, while phylosymbiotic signals in atyids and pandalids were only detected in fewer than half of the tests. A weak phylogenetic signal was detected in the predicted functions of the penaeid gut microbiota. However, the functional diversities of the two caridean groups were not significantly related to host phylogeny. Our observations of a parallelism in the taxonomy of the gut microbiota with host phylogeny for all shrimp groups examined and in the predicted functions for the penaeid shrimps indicate a tight host-microbial relationship during evolution.

Dipeptidyl Peptidase-4 deficiency effectively protects the brain and neurological function in rodent after acute Hemorrhagic Stroke.

This study tested the hypothesis that abrogated dipeptidyl peptidase-4 (DPP4) activity played a crucial role on reducing stroke volume and preserving neurological function in rodent after acute hemorrhagic stroke (AHS). Animals (n=6/each group) were categorized into group 1 (sham-control of F344 rat), group 2 (sham-control of DPP4-deficiency rat), group 3 [AHS by right cerebral injection of autologous blood (100 µL) in F344 rat], group 4 (AHS + sitagliptin/600 mg/kg 3 h prior to and at 3 h then once per day after AHS) and group 5 (AHS in DPP4-deficiency rat). The results of corner test showed the neurological function was significantly improved from days 3, 7, and 14 in groups 4 and 5 than in group 3 (all p<0.001). By days 1 and 14 after AHS procedure, the circulating levels of SDF-1α and GLP-1 were significantly increased from groups 1/2 to group 5 (all p<0.001), whereas circulating DPP4 activity was significantly increased in group 3 than other groups (all p<0.001). The brain ischemic area (BIA) was highest in group 3, lowest in groups 1/2 and significantly lower in group 5 than in group 4 (all p<0.0001). The protein expressions of oxidative-stress/inflammatory/apoptotic/cell-proliferation signaling, and the cellular expressions of inflammatory/DNA-damaged biomarkers exhibited a similar pattern to BIA among the groups (all p<0.01). In conclusion, deprivation of DPP4 activity protected the brain from AHS damage and preserved neurological function.

Is the Yale Global Tic Severity Scale a valid tool for parent-reported assessment in the paediatric population? A prospective observational study in Taiwan.

OBJECTIVE: The Yale Global Tic Severity Scale (YGTSS) is the most commonly used clinician-rated evaluation tool for Tourette syndrome (TS), with established reliability and validity. This study aims to determine whether the YGTSS is a valid parent-reported assessment in the TS population. DESIGN: A prospective cohort study. SETTING: A major medical centre in Taiwan. METHODS: A total of 594 patients were enrolled. A revised traditional Chinese version of the YGTSS was made available to parents via Google docs. Parents were encouraged to complete the YGTSS the day before each outpatient clinic visit. At each visit, a paediatric neurology fellow also administered the YGTSS assessment. We investigated whether differences in scores between physicians and parents changed as the number of parent evaluations increased. The results of the physician assessments were also taken as the expert standard for evaluating the sensitivity and specificity of the parent-reported assessments was conducted for the same visit. RESULTS: The differences in the YGTSS scores between participants and physicians were small. The mean difference in the total assessment score was 4.15 points. As the number of times the parent evaluation was performed increased, the difference between the parent and physician scores decreased. Discrimination of moderate-to-severe attacks was good using the parent-assessed YGTSS (area under the receiver operating characteristic curve, 0.858; 95% CI 0.839 to 0.876). The sensitivity for detecting a moderate-to-severe attack by YGTSS parent assessment was 79.7% (95% CI 76.6 to 82.8), and the specificity was 91.8% (95% CI 89.9 to 93.7). CONCLUSION: The parent-reported YGTSS is a promising tool for TS assessment, demonstrating good discriminative ability for disease severity, with user precision increasing with experience.

New records of Benthesicymus Bate, 1881 (Dendrobranchiata, Penaeoidea, Benthesicymidae) from the abyssal depths of Taiwan.

The deep-sea Benthesicymus shrimps generally inhabit waters deeper than 1000 m deep. Recent deep-sea cruises off Taiwan collected two species of Benthesicymus Bate, 1881 from the abyssal depths greater than 3,000 m. They are B.crenatus Bate, 1881 and B.laciniatus Rathbun, 1906. Both of them are new records for Taiwan, with B.crenatus also representing the deepest (5,314 m) marine animal so far known for the island. The major distinguishing characters of these two species are described and illustrated.

Long-term Therapeutic Effects of Extracorporeal Shock Wave-Assisted Melatonin Therapy on Mononeuropathic Pain in Rats.

We evaluated the ability of extracorporeal shock wave (ECSW)-assisted melatonin (Mel) therapy to offer an additional benefit for alleviating the neuropathic pain (NP) in rats. Left sciatic nerve was subjected to chronic constriction injury (CCI) to induce NP. Animals (n = 30) were randomized into group 1 (sham-operated control), group 2 (CCI only), group 3 (CCI + ECSW), group 4 (CCI + Mel) and group 5 (CCI + ECSW + Mel). By days 15, 22 and 29 after CCI, the thermal paw withdrawal latency (TPWL) and mechanical paw withdrawal threshold (MPWT) were highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but they showed no difference between the later two groups (all p < 0.0001). The protein expressions of inflammatory (TNF-α, NF-κB, MMP-9, IL-1ß), oxidative-stress (NOXs-1, -2, -4, oxidized protein), apoptotic (cleaved-caspase3, cleaved-PARP), DNA/mitochondrial-damaged (γ-H2AX/cytosolic-cytochrome C), microglia/astrocyte activation (ox42/GFAP), and MAPKs [phosphorylated (p)-p38, p-JNK, p-ERK] biomarkers in dorsal root ganglia neurons (DRGs) and in spinal dorsal horn were exhibited an opposite pattern of TPWL among the five groups (all p < 0.0001). Additionally, protein expressions of Nav.1.3, Nav.1.8 and Nav.1.9 in sciatic nerve exhibited an identical pattern to inflammation among the five groups (all p < 0.0001). The numbers of cellular expressions of MAPKs (p-ERK1/2+/peripherin + cells, p-ERK1/2+/NF200 + cells and p-JNK+/peripherin + cells, p-JNK+/NF200 + cells) and voltage-gated sodium channels (Nav.1.8+/peripherin + cells, Nav.1.8+/NF200 + cells, Nav.1.9+/peripherin + cells, Nav.1.9+/NF200 + cells) in small and large DRGs displayed an identical pattern to inflammation among the five groups (all p < 0.0001). In conclusion, the synergistic effect of combined ECSW-Mel therapy is superior to either one alone for long-term improvement of mononeuropathic pain-induced by CCI in rats.

On Plesionika persica (Kemp, 1925) and P. reflexa Chace, 1985 (Crustacea: Decapoda: Pandalidae) from India.

The availability of Indian specimens of Plesionika persica (Kemp, 1925) and P. reflexa Chace, 1985 provided more information on the taxonomy around these two species. Moreover, it is the first record of P. persica to India. Although P. taiwanica Chan and Yu, 2000 is superficially rather similar to P. persica, there are many differences between them and probably it is inappropriate to establish a species group for these two species. It is likely that all previous records of P. ensis (A. Milne-Edwards, 1881) from India actually represent P. reflexa Chace, 1985. Nevertheless, the present Indian specimens of P. reflexa have more than 10% COI sequence divergence from the topotypic materials of both P. ensis and P. reflexa, and the epipods at the pereiopods III and IV reduced or absent. This data further highlights the confusing taxonomy in the "P. ensis" group.

Exhaled nitric oxide helps discriminating asthmatic children with and without positive specific IgE to aeroallergens.

BACKGROUND: Aeroallergen sensitization may predict higher fractional exhaled nitric oxide (FeNO) levels. OBJECTIVE: We evaluate cut-off values of FeNO in asthmatic children with and without positive specific immunoglobulin E (IgE) to at least one of 5 aeroallergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat, dog, and cockroach). METHODS: 564 patients with asthma and allergic rhinitis (AR) aged 5 to 18 years were enrolled into two groups. Sensitized group included 378 children with positive IgE to at least one of 5 inhaled allergens. Non-sensitized group included 186 children. Pulmonary function tests, FeNO, eosinophil counts, and IgE levels were examined. Patients were divided into preschool age (5~6 years old), elementary school children (7~11 years old) and adolescents (12~18 years old). RESULTS: In preschool children, FeNO≥15.5 ppb differentiates between non-sensitized and sensitized groups. (sensitivity 54.3%; specificity 87.5%; positive predictive value (PPV) 86.2%; negative predictive value (NPV) 57.1%; area under receiver operating characteristic curve (AUC) 0.72) Among elementary school children, the cut-off value of FeNO≥19.5 ppb showed sensitivity 66.4%; specificity 85.8%; PPV 90.5%; NPV 55.7%; AUC 0.81. In adolescents, FeNO≥27.5 ppb showed sensitivity 60.2%; specificity 85.4%; PPV 91.2%; NPV 46.1%; AUC 0.76. CONCLUSION: In asthmatic children, aeroallergen sensitization appears to contribute to higher FeNO levels than those not sensitized. Cut-off values of FeNO which well discriminate asthmatic children with and without aeroallergen sensitization should be chose according to different ages.

A new slipper lobster of the genus Petrarctus Holthuis, 2002 (Crustacea, Decapoda, Scyllaridae) from Southwest coast of India.

A new species of slipper lobster of the genus Petrarctus Holthuis, 2002 was discovered from southwestern India during a survey of deep sea crustaceans. The new species closely resembles P. veliger Holthuis, 2002 from the Andaman Sea and western Pacific but differs mainly in the color marking on abdominal somite I, having a relatively lower cardiac tooth but with better developed tubercles on the abdomen, as well as a differently shaped anterior part of the thoracic sternum. Molecular genetic analysis also confirms the distinct taxonomic status of the new species. To fix the identity of the type species of the genus, a neotype of P. rugosus (H. Milne Edwards, 1837) was selected from a recently collected Indian specimen with color and genetic information.

Photophore counts in the deep-sea commercial shrimp Aristeus alcocki Ramadan, 1938 (Crustacea: Decapoda: Aristeidae), with a revised key to the Indo-West Pacific species of the genus.

The availability of abundant fresh material of Aristeus alcocki Ramadan, 1938 from India allowed the evaluation of the variation in the numbers of photophores on the pereiopods in this species, as well as other diagnostic characters for species discrimination. Although the pereiopodal photophore counts in A. alcocki largely overlap with those of A. semidentatus Bate, 1888, it is found that A. alcocki is unique in the Indo-West Pacific species of the genus by the lower end of the cervical carina considerably farther away from the branchiostegal carina. Molecular genetic analysis confirmed the distinct taxonomic status of the six currently known species in this genus from the Indo-West Pacific and a revised key is provided for distinguishing them.

Further records of the deep-sea pandalid shrimp Heterocarpus chani Li, 2006 (Crustacea, Decapoda, Caridea) from southern India.

The commercial deep-sea caridean shrimp Heterocarpus gibbosus Spence Bate, 1888 has long been recorded from India and constitutes an important part of the catches in the context of the further development of deep-sea fisheries in India. A recent survey in some deep-sea fishing ports in southern India, however, revealed that all material previously reported as "H. gibbosus" is actually a misidentification of its closely related species H. chani Li, 2006, which has only recently been reported from India. More detailed comparisons allowed the discovery of more distinctive characters between H. chani and H. gibbosus.

Combination therapy with extracorporeal shock wave and melatonin markedly attenuated neuropathic pain in rat.

This study tested the hypothesis that combination therapy using extracorporeal shock wave (ECSW)-melatonin (Mel) was superior to either alone at ameliorating neuropathic pain (NP). NP was induced by chronic constriction injury (CCI) to the left sciatic nerve in rats. Animals were categorized into sham control (group 1), CCI only (group 2), CCI-ECSW (group 3), CCI-Mel (group 4) and CCI-ECSW-Mel (group 5). By days 2 and 8 after CCI, the mechanical paw withdrawal threshold (MPWT)/thermal paw withdrawal latency (TPWL) were highest in group 2, lowest in group 1, significantly lower in group 5 than in groups 3 and 4 (all p<0.0001), and not significantly different between groups 3 and 4. The protein expressions of inflammatory (TNF-α/NF-κB/MMP-9/IL-1ß/GFAP/ox42), oxidative-stress (NOX-1/NOX-2/NOX-4/oxidized protein), DNA/mitochondrial-damaged (γ-H2AX/cytosolic mitochondria), apoptotic (cleaved capase-3/PARP), and MAPK family biomarkers (p-P38/p-JNK/p-ERK1/2) in dorsal root ganglia and spinal dorsal horn expressed a similar pattern of MPWT/TPWL among the five groups, except for significantly higher in group 4 than in group 3 (all p<0.0001). The protein expressions of Nav.1.3, Nav.1.8 and Nav.1.9 in sciatic nerve displayed an identical pattern to inflammation among the five groups (all p<0.001). Pain facilitated cellular expressions (p-P38+/peripherin+ cells, P38+/NF200+ cells) displayed an identical pattern to inflammation among the five groups (all p<0.0001). In conclusion, ECSW-Mel combination therapy markedly ameliorated NP induced by CCI.