The effect of Plasmodium berghei and Trypanosoma brucei infections on the immune expulsion of the nematode Trichuris muris from mice

The effects of concurrent P. berghei or T. brucei infections on the immune expulsion of primary and challenge infections of T. muris from CFLP strain mice have been examined. CFLP mice usually expel the nematode 18–21 days after a primary infection and within 4–6 days after a challenge infection. Both acute malaria and trypanosome infections initiated at the same time as the T. muris infection suppressed worm expulsion; when the protozoal infections were started 7 days after the T. muris infection worm expulsion was suppressed in a proportion of the mice. Acute trypanosome and malaria infections delayed the expulsion of a challenge infection from immune mice, but in the case of P. berghei the delay was short-lived.     

Pretreatment CT and PET radiomics predicting rectal cancer patients in response to neoadjuvant chemoradiotherapy

BackgroundThe purpose of this study was to characterize pre-treatment non-contrast computed tomography (CT) and ¹⁸F-fluorodeoxyglucose positron emission tomography (PET) based radiomics signatures predictive of pathological response and clinical outcomes in rectal cancer patients treated with neoadjuvant chemoradiotherapy (NACR T).Materials and methodsAn exploratory analysis was performed using pre-treatment non-contrast CT and PET imaging dataset. The association of tumor regression grade (TRG) and neoadjuvant rectal (NAR) score with pre-treatment CT and PET features was assessed using machine learning algorithms. Three separate predictive models were built for composite features from CT + PET.ResultsThe patterns of pathological response were TRG 0 (n = 13; 19.7%), 1 (n = 34; 51.5%), 2 (n = 16; 24.2%), and 3 (n = 3; 4.5%). There were 20 (30.3%) patients with low, 22 (33.3%) with intermediate and 24 (36.4%) with high NAR scores. Three separate predictive models were built for composite features from CT + PET and analyzed separately for clinical endpoints. Composite features with α = 0.2 resulted in the best predictive power using logistic regression. For pathological response prediction, the signature resulted in 88.1% accuracy in predicting TRG 0 vs. TRG 1–3; 91% accuracy in predicting TRG 0–1 vs. TRG 2–3. For the surrogate of DFS and OS, it resulted in 67.7% accuracy in predicting low vs. intermediate vs. high NAR scores.ConclusionThe pre-treatment composite radiomics signatures were highly predictive of pathological response in rectal cancer treated with NACR T. A larger cohort is warranted for further validation.     

Distinct distribution of HPV types among cancer-free Afro-Caribbean women from Tobago

Human papillomavirus (HPV), a sexually transmitted virus causes cervical carcinomas, and is associated with ∼36% of oropharyngeal tumours where HPV16 is the predominant genotype. The cervical cancer incidence rate in Trinidad and Tobago is about two times higher than the worldwide rate. We have for the first time determined the prevalence and type distribution of cervical HPV infections among cancer-free Afro-Caribbean women from Tobago, and compared it with the HPV subtypes observed in their oral cavity. Thirty-five per cent of the women were cervical HPV positive. The most common high-risk type detected in the cervix was HPV45 rather than HPV16 and 18. The prevalence of HPV infection in the oral mucosa was 6.6%. The distribution of HPV genotypes in healthy Tobagonian women is different from that reported in studies conducted in European and North American populations. This may have important implications for vaccine introduction in this and other Afro-Caribbean countries.     

Insertion of scFv into the hinge domain of full-length IgG1 monoclonal antibody results in tetravalent bispecific molecule with robust properties

By simultaneous binding two disease mediators, bispecific antibodies offer the opportunity to broaden the utility of antibody-based therapies. Herein, we describe the design and characterization of Bs4Ab, an innovative and generic bispecific tetravalent antibody platform. The Bs4Ab format comprises a full-length IgG1 monoclonal antibody with a scFv inserted into the hinge domain. The Bs4Ab design demonstrates robust manufacturability as evidenced by MEDI3902, which is currently in clinical development. To further demonstrate the applicability of the Bs4Ab technology, we describe the molecular engineering, biochemical, biophysical, and in vivo characterization of a bispecific tetravalent Bs4Ab that, by simultaneously binding vascular endothelial growth factor and angiopoietin-2, inhibits their function. We also demonstrate that the Bs4Ab platform allows Fc-engineering similar to that achieved with IgG1 antibodies, such as mutations to extend half-life or modulate effector functions.     

Weekly vs. tri-weekly cisplatin based chemoradiation in carcinoma cervix: a prospective randomized study of toxicity and compliance

BackgroundAddition of chemotherapy to radiation has improved 5-year survival by 6%. However, the optimal dose and schedule of concurrent cisplatin is not well defined, though widely accepted practice is the weekly schedule of 40 mg/m² for 5 weeks. Repeated admissions for weekly cisplatin drain the limited resources in high volume centres. We intended to study the compliance and toxicity of two cisplatin schedules in our patients diagnosed with carcinoma cervix.Materials and methodsBetween 2007–2011, 212 patients, histologically proven squamous cell carcinoma with stages IIB to IIIB were randomized into two arms. All patients were planned for external beam radiotherapy 45 Gy/25 frs over 5 weeks followed by Intracavitary or Interstitial brachytherapy to a total BED dose of 75–85 Gy. Single agent cisplatin given concomitantly, was scheduled weekly (40 mg/m²/cycle, 5 cycles) in an arm A and three weekly (100 mg/m²/cycle, 2 cycles) in an arm B. Toxicity and compliance were evaluated weekly according to the RTOG guidelines. Analysis of the compiled data was done using SSPS version 20.ResultsOf the evaluable 212, 109 patients received weekly cisplatin chemotherapy and 103 patients received three weekly cisplatin. The most common acute toxicity observed was grade I–II leucopoenia. The upper and lower gastrointestinal reactions were high in three weekly arms, which was statistically significant (57% and 42.7%, p < 0.05). Proctitis was observed in 10% of patients in both of the arms and only two patients had Gr1 Cystitis after 6 months of treatment.ConclusionsTri-weekly cisplatin based concurrent chemoradiation can be adopted in high volume centres with manageable haematological and gastrointestinal acute toxicities.     

同步放化疗联合深部热疗治疗中晚期宫颈癌的临床疗效观察

目的观察放化疗联合深部热疗治疗中晚期宫颈癌的临床疗效及不良反应。方法选取本院收治的Ⅱb—Ⅲb期宫颈癌患者70例,分为同步放化疗联合深部热疗组（试验组）和同步放化疗组（对照组）,对照组进行根治性放射治疗,放疗第1天开始行化疗,顺铂40mg静脉滴注1d,化疗6个周期,每周重复。试验组：放化疗方法同对照组,于化疗当天行盆腹腔深部热疗（HG-2000体外高频热疗机）,每次热疗60min,每周1次,共4次。于热疗后1h内行放射治疗。结果两组局部肿瘤消退情况、近期疗效、肿瘤局部控制情况、1年期无瘤生存情况比较,差异有统计（P〈0．05）。两组不良反应比较无统计差异。结论同步放化疗联合深部热疗可以提高患者近期疗效,且无严重的并发症,是中晚期宫颈癌治疗中的一种安全有效的模式,值得进一步研究。     

Individual Effects of Seasonal Changes,Visitor Density,and Concurrent Bear Behavior on Stereotypical Behaviors in Captive Polar Bears (Ursus maritimus)

Stereotypical behaviors in captive polar bears (Ursus maritimus) can be detrimental to their welfare. These behaviors can be reduced through enrichment programs but are often not completely eliminated, so identifying potential triggers is important. The present study investigated the influences of seasonal changes, visitor density, and concurrent bear activity on stereotypical behaviors exhibited by 3 captive polar bears at the Toronto Zoo. All bears exhibited these behaviors; however, individual differences were found in duration and form. The male exhibited less stereotypical behavior during spring, and the females exhibited less stereotypical behavior during winter. An increase in visitor density was associated with more stereotypical behavior in 1 female but less stereotypical behavior in the other 2 bears. All bears engaged in more stereotypical behaviors when the other bears were inactive, and 1 female engaged in more stereotypical behaviors when the other bears were out of sight. Further, when conspecifics were active, all bears engaged in less stereotypical behaviors. Given the variability among individual bears, future enrichment programs must be tailored to the needs of individuals to maximize efficacy.     

Clinical significance of risk stratification of esophageal squamous cell carcinoma after neoadjuvant chemoradiation and surgery

ObjectiveNowadays, there were few studies reporting the risk stratification of patients with esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemoradiation (NCRT) and surgery. We aimed to establish a simple risk stratification to help postoperative detection and adjuvant treatment.MethodsWe included 146 patients with locally advanced ESCC who received NCRT followed by esophagectomy. The impacts of clinicopathological factors on overall survival (OS) and disease-free survival (DFS) were analyzed. The recurrence site, time, and frequency were recorded as well.ResultsThe median follow-up was 53 months. The pathological complete respond (pCR) group demonstrated better 5-year OS and DFS (78.6% and 77.0%) than the non-pCR group (44.8% and 35.2%, all P < 0.005). Multivariate analysis for the non-pCR group revealed perineural invasion (PNI) (HR:2.296, P = 0.013) and ypTNM stage (I/II vs III/IV) (HR:1.972, P = 0.046) were considered as independent unfavorable factors affecting OS, while PNI (HR:1.866, P = 0.045) and lymph vessel invasion (LVI) (HR:3.370, P < 0.001) were considered as independent adverse factors for DFS. Based on clinicopathological factors (including pCR, ypTNM stage, PNI, LVI), patients were divided into the low-risk (pCR), mediate-risk (non-pCR without PNI, LVI, stage III/IV), high-risk (non-pCR with one factor of PNI, LVI or stage III/IV (n = 45)), highest risk (non-pCR with two or more factors of PNI, LVI or stage III/IV) groups. The corresponding 5-year OS rates were 78.6%, 60.4%, 49.6%, 18.6%, respectively (P < 0.005) and 5-year DFS rates were 77.0%, 46.9%, 41.1%, 12.1%, respectively (P < 0.005). Adjuvant chemotherapy may improve survival in high or highest risk groups of patients with low prognostic nutritional index (< 49).ConclusionsA novel risk stratification based on clinicopathological factors may be conducive to postoperative surveillance and guide adjuvant chemotherapy.     

Trypanosoma musculi with Trichinella spiralis or Heligmosomoides polygyrus: concomitant infections in the mouse

Inbred mice infected with Trypanosoma musculi displayed wide variations in peak blood parasitemia. The most susceptible mice were C3H and A strain, while Balb/c, C57B1/6, and the related congenic B10 strains were the most resistant. The effect of an intestinal infection with either Trichinella spiralis or Heligmosomoides polygyrus on proliferation of T. musculi was investigated. T. spiralis infections given at the same time or up to 45 days before a T. musculi infection always caused an increase in blood parasitemia in C3H mice. Maximum increases were observed when T. spiralis infections preceded T. musculi by 5-10 days. In all mouse strains examined, dual infections increased maximum parasitemia by two- to four-fold, regardless of the degree of resistance of that mouse strain to either T. musculi or T. spiralis. This suggested that the immunological "cost" of a T. spiralis infection was the same for strains that were strong or weak responders to a primary infection with T. spiralis. In contrast, infection with H. polygyrus did not promote T. musculi parasitemia over the level of a single infection. The increase in blood parasitemia in T. spiralis-infected mice was largely due to the intestinal adult worm, but migratory larvae and mature muscle larvae also stimulated increased parasitemias. The increase in parasitemia was proportionate to the dose of T. spiralis, and the sex of the host did not affect the blood trypanosome level.     

Eimeria nieschulzi and Trichinella spiralis: Analysis of concurrent infection in the rat

The effects of concurrent primary infection of the rat with Eimeria nieschulzi and Trichinella spiralis on the number of oocysts of E. nieschulzi shed by the host and on the number, distribution, and fecundity of adult T. spiralis were analyzed. When rats were initially infected with E. nieschulzi followed 9 days later by infection with T. spiralis there occurred a significant decrease in the total numbers of adult worms in the small intestine, a significant shift in the position of these worms along the length of the small gut, a decrease in the fecundity of adult female worms, and a decrease in muscle parasitism when compared with rats infected with T. spiralis alone. When rats were initially infected with T. spiralis, followed 9 days later by infection with E. nieschulzi, there occurred a significant decrease in the numbers of oocysts shed over 24 hr on Days 7, 9, and 11 postinfection below that seen with rats infected only with Eimeria. These changes are discussed in terms of the enteropathophysiologic lesions and enteric inflammation known to occur during infections with these two parasites.