Response of Laryngeal and Tracheo-Bronchial Surface Lining to Inhaled Cigarette Smoke in Normal and Vitamin A-Deficient Rats: A Scanning Electron Microscopic Study.

The effects on surface morphology of airway epithelium of cigarette smoke (CS) inhalation alone (experiments one and two) or of CS in combination with hypovitaminosis A (experiment two) was investigated using specific pathogen free rats. Eight morphologically distinct cell types were distinguished overall. Apart from atypical squamous lesions each of the other cell types could be found in varying proportions in all experimental groups. CS alone caused an increase in the frequency with which intra-lumenal mucus was seen and an increase in the occurrence of secretory cells of types IV (i.e.,\u27merocrine\u27) and V (i.e.,\u27apocrine\u27). In experiment one, the area of trachea covered by cilia as determined by point counting increased significantly (P\u3c0.01). Hypovitaminosis A was induced by lowering the dietary intake of vitamin A to a minimum, defined level. Rats showed an approximately 75% decrease in plasma retinol levels and a 95-100% decrease in hepatic stores of vitamin A. At this level, hypovitaminosis A alone had no significant effect on airway epithelial morphology. Foci of squamous metaplasia (squamous cells of type VIIIa) were found in all groups but extensive squamous metaplasia of the larynx and squamous lesions of atypical appearance (type VIIIb) were found only in the vitamin deficient group exposed to CS. The results suggest the synergistic effects of reduced vitamin A and CS may be important in the induction of atypical squamous changes which may predispose the airway to the development of squamous carcinoma

On the origin of aurorae on Mars

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95268/1/grl20829.pd

Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial

The present analysis, carried out in the context of a randomized phase III trial, confirms superior outcomes for breast cancer patients for whom chemotherapy induces pathological complete response (pCR) after adjusting for other important prognostic factors. In contrast, when tumours do not achieve pCR, patients have a higher risk of relapse. This effect is observed in all intrinsic subtypes and justifies the current interest in post-neoadjuvant trial

Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial

Background: Patients with brain metastases (BM) from human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent a difficult-to-treat population. Trastuzumab emtansine (T-DM1) has shown potential activity in this subset of patients in small clinical series. Patients and methods: KAMILLA is an ongoing, phase IIIb study of T-DM1 in patients with HER2-positive locally advanced/metastatic breast cancer with prior HER2-targeted therapy and chemotherapy. Patients received T-DM1 3.6 mg/kg every 3 weeks (intravenously) until unacceptable toxicity, withdrawal of consent, or disease progression. Tumor response and clinical outcomes in patients with baseline BM were evaluated in this post hoc, exploratory analysis. The main outcome measures were best overall response rate (complete response + partial response) and clinical benefit rate (complete response + partial response + stable disease lasting =6 months) by RECIST v1.1 criteria, progression-free survival, overall survival, and safety. Results: Of 2002 treated patients, 398 had baseline BM. In 126 patients with measurable BM, the best overall response rate and clinical benefit rate were 21.4% [95% confidence interval (CI) 14.6–29.6] and 42.9% (95% CI 34.1–52.0), respectively. A reduction in the sum of the major diameters of BM =30% occurred in 42.9% (95% CI 34.1–52.0), including 49.3% (95% CI 36.9–61.8) of 67 patients without prior radiotherapy to BM. In the 398 patients with baseline BM, median progression-free survival and overall survival were 5.5 (95% CI 5.3–5.6) months and 18.9 (95% CI 17.1–21.3) months, respectively. The adverse event profile was broadly similar in patients with and without baseline BM, although nervous system adverse events were more common in patients with [208 (52.3%)] versus without [701 (43.7%)] baseline BM. Conclusion: This exploratory analysis of patients with HER2-positive metastatic breast cancer and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting

Finitely-Generated Projective Modules over the Theta-deformed 4-sphere

We investigate the "theta-deformed spheres" C(S^{3}_{theta}) and C(S^{4}_{theta}), where theta is any real number. We show that all finitely-generated projective modules over C(S^{3}_{theta}) are free, and that C(S^{4}_{theta}) has the cancellation property. We classify and construct all finitely-generated projective modules over C(S^{4}_{\theta}) up to isomorphism. An interesting feature is that if theta is irrational then there are nontrivial "rank-1" modules over C(S^{4}_{\theta}). In that case, every finitely-generated projective module over C(S^{4}_{\theta}) is a sum of a rank-1 module and a free module. If theta is rational, the situation mirrors that for the commutative case theta=0.Comment: 34 page

Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin

<p>Abstract</p> <p>Background</p> <p>Acute cutaneous neurogenic inflammation initiated by activation of transient receptor potential vanilloid-1 (TRPV₁) receptors following intradermal injection of capsaicin is mediated mainly by dorsal root reflexes (DRRs). Inflammatory neuropeptides are suggested to be released from primary afferent nociceptors participating in inflammation. However, no direct evidence demonstrates that the release of inflammatory substances is due to the triggering of DRRs and how activation of TRPV₁receptors initiates neurogenic inflammation via triggering DRRs.</p> <p>Results</p> <p>Here we used pharmacological manipulations to analyze the roles of TRPV₁and neuropeptidergic receptors in the DRR-mediated neurogenic inflammation induced by intradermal injection of capsaicin. The degree of cutaneous inflammation in the hindpaw that followed capsaicin injection was assessed by measurements of local blood flow (vasodilation) and paw-thickness (edema) of the foot skin in anesthetized rats. Local injection of capsaicin, calcitonin gene-related peptide (CGRP) or substance P (SP) resulted in cutaneous vasodilation and edema. Removal of DRRs by either spinal dorsal rhizotomy or intrathecal administration of the GABA_Areceptor antagonist, bicuculline, reduced dramatically the capsaicin-induced vasodilation and edema. In contrast, CGRP- or SP-induced inflammation was not significantly affected after DRR removal. Dose-response analysis of the antagonistic effect of the TRPV₁receptor antagonist, capsazepine administered peripherally, shows that the capsaicin-evoked inflammation was inhibited in a dose-dependent manner, and nearly completely abolished by capsazepine at doses between 30–150 μg. In contrast, pretreatment of the periphery with different doses of CGRP_8–37(a CGRP receptor antagonist) or spantide I (a neurokinin 1 receptor antagonist) only reduced the inflammation. If both CGRP and NK₁receptors were blocked by co-administration of CGRP_8–37and spantide I, a stronger reduction in the capsaicin-initiated inflammation was produced.</p> <p>Conclusion</p> <p>Our data suggest that 1) the generation of DRRs is critical for driving the release of neuropeptides antidromically from primary afferent nociceptors; 2) activation of TRPV₁receptors in primary afferent nociceptors following intradermal capsaicin injection initiates this process; 3) the released CGRP and SP participate in neurogenic inflammation.</p