Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by the transcription factors Oct4, Sox2, and Klf4 in combination with c-Myc. Recently, Sox2 plus Oct4 was shown to reprogram fibroblasts and Oct4 alone was able to reprogram mouse and human neural stem cells (NSCs) into iPS cells. Here, we report that Bmi1 leads to the transdifferentiation of mouse fibroblasts into NSC-like cells, and, in combination with Oct4, can replace Sox2, Klf4 and c-Myc during the reprogramming of fibroblasts into iPS cells. Furthermore, activation of sonic hedgehog signaling (by Shh, purmorphamine, or oxysterol) compensates for the effects of Bmi1, and, in combination with Oct4, reprograms mouse embryonic and adult fibroblasts into iPS cells. One- and two-factor iPS cells are similar to mouse embryonic stem cells in their global gene expression profile, epigenetic status, and in vitro and in vivo differentiation into all three germ layers, as well as teratoma formation and germline transmission in vivo. These data support that converting fibroblasts with Bmi1 or activation of the sonic hedgehog pathway to an intermediate cell type that expresses Sox2, Klf4, and N-Myc allows iPS generation via the addition of Oct4.
reprogramming; transdifferentiation; neural stem cells; induced pluripotent stem cells; Bmi1; Oct4
Objective. This study aimed to assess the interval changes of thyroid colloid cysts (TCCs) by performing long-term ultrasound (US) follow-up examinations. Methods. From 2007 to 2008, 437 patients underwent a lobectomy for the treatment of papillary thyroid microcarcinoma. Among them, 268 patients underwent 4 or more postoperative US follow-ups after surgery. This study investigated the prevalence and interval changes of TCCs ≥3 mm by using US follow-ups. Results. Among 268 patients, 35 (13.1%) had TCCs ≥3 mm by a preoperative thyroid US, and 6 (2.2%) had newly detected TCCs at a US follow-up. Through long-term US follow-up, the interval changes for TCCs were classified as follows: no interval change (n = 8), gradual increase (n = 8), gradual decrease (n = 5), positive fluctuation (n = 3), negative fluctuation (n = 6), disappearance (n = 5), and new detection (n = 6). None of the TCC cases had a TCC that was ≥10 mm at its largest diameter, and no patient complained of any relevant symptoms pertaining to the TCCs. Conclusions. In this study, TCCs demonstrated various interval changes, but no abrupt increase was found or acute onset of symptoms occurred.
Objective. This study aimed to evaluate the CT features of incidentally detected DTD in the patients who underwent thyroidectomy and to assess the diagnostic accuracy of CT diagnosis. Methods. We enrolled 209 consecutive patients who received preoperative neck CT and subsequent thyroid surgery. Neck CT in each case was retrospectively investigated by a single radiologist. We evaluated the diagnostic accuracy of individual CT features and the cut-off CT criteria for detecting DTD by comparing the CT features with histopathological results. Results. Histopathological examination of the 209 cases revealed normal thyroid (n = 157), Hashimoto thyroiditis (n = 17), non-Hashimoto lymphocytic thyroiditis (n = 34), and diffuse hyperplasia (n = 1). The CT features suggestive of DTD included low attenuation, inhomogeneous attenuation, increased glandular size, lobulated margin, and inhomogeneous enhancement. ROC curve analysis revealed that CT diagnosis of DTD based on the CT classification of “3 or more” abnormal CT features was superior. When the “3 or more” CT classification was selected, the sensitivity, specificity, positive and negative predictive values, and accuracy of CT diagnosis for DTD were 55.8%, 95.5%, 80.6%, 86.7%, and 85.6%, respectively. Conclusion. Neck CT may be helpful for the detection of incidental DTD.
We report an extremely rare case of papillary thyroid microcarcinoma (PTMC) in the thyroid Epub ahead of print pyramidal lobe (TPL). A 48-year-old woman underwent ultrasound-guided fine-needle aspiration for a small thyroid nodule in the right lobe in local clinic, and it revealed a malignant cytology. On preoperative ultrasonography for tumor staging in our hospital, another small suspiciously malignant hypoechoic nodule was detected in the left TPL. Total thyroidectomy and central nodal dissection were performed. Histopathology confirmed PTMCs in the left TPL and both thyroid lobes. Ultrasonography for TPL should be required for complete evaluation of possible multifocality of thyroid malignancy.
Thyroid nodule; Pyramidal lobe; Papillary thyroid microcarcinoma; Ultrasonography
We describe a female insulinoma patient who presented with recurrent attacks of abnormal behavior, confusion, and seizure. Her interictal EEG showed epileptiform discharges on the left temporal area, therefore she was initially misdiagnosed as temporal lobe epilepsy. In the video-EEG monitoring, hypoglycemic state was detected during the seizure attack, so the right diagnosis was made after the endocrinologic investigations. After surgical removal of the tumor, the patient became seizure-free, and no abnormality was found in the follow-up EEG after six months. Since insulinoma shares some common clinical and EEG features with complex partial seizure of temporal lobe origin, insulioma should be included in the differential diagnosis for medically intractable temporal lobe epilepsy.
Insulinoma; Hypoglycemia; EEG; Temporal lobe epilepsy
There has been no study to compare the diagnostic accuracy of an experienced radiologist with a trainee in nasal bone fracture.
To compare the diagnostic accuracy between conventional radiography and computed tomography (CT) for the identification of nasal bone fractures and to evaluate the interobserver reliability between a staff radiologist and a trainee.
Patients and Methods
A total of 108 patients who underwent conventional radiography and CT after acute nasal trauma were included in this retrospective study. Two readers, a staff radiologist and a second-year resident, independently assessed the results of the imaging studies.
Of the 108 patients, the presence of a nasal bone fracture was confirmed in 88 (81.5%) patients. The number of non-depressed fractures was higher than the number of depressed fractures. In nine (10.2%) patients, nasal bone fractures were only identified on conventional radiography, including three depressed and six non-depressed fractures. CT was more accurate as compared to conventional radiography for the identification of nasal bone fractures as determined by both readers (P <0.05), all diagnostic indices of an experienced radiologist were similar to or higher than those of a trainee, and κ statistics showed moderate agreement between the two diagnostic tools for both readers. There was no statistical difference in the assessment of interobserver reliability for both imaging modalities in the identification of nasal bone fractures.
For the identification of nasal bone fractures, CT was significantly superior to conventional radiography. Although a staff radiologist showed better values in the identification of nasal bone fracture and differentiation between depressed and non-depressed fractures than a trainee, there was no statistically significant difference in the interpretation of conventional radiography and CT between a radiologist and a trainee.
Nasal Bone, Fractures, Bone; Radiography
Background and Purpose:
The ketogenic diet was formulated to mimic the biochemical changes seen upon fasting, specifically the formation of ketone bodies. Recent research data suggest that the anticonvulsant efficacy of the KD may be due in part to the direct actions of ketone bodies. This study was designed to investigate the anticonvulsant effects of β-hydroxybutyrate (BHB) on pilocarpine-induced seizures in mature mice.
Eighty-two male ICR mice at postnatal day 49 were used. All mice were pretreated with scopolamine methylbromide prior to pilocarpine injection. Experimental mice (n=42) were injected intraperitoneally with BHB (20 mmol/kg) 15 min prior to pilocarpine administration, while control animals (n=40) with normal saline. Pilocarpine (300 mg/kg) was administered intraperitoneally and mice were monitored for 2 h after pilocarpine injection.
All mice developed typical seizure behaviors. The mean (±SD) latency to the onset of seizures was significantly prolonged in the BHB-treated mice compared with controls (4.83±1.95 min vs. 3.67±1.90 min, p<0.01).
This study demonstrates that treatment with BHB prolongs the latency to the onset of seizures induced by pilocarpine in mature mice and suggests that BHB, one of the ketone bodies, may have direct anticonvulsant effects.
Ketone body; 3-hydroxybutyric acid; Pilocarpine; Mice; Seizure
Atopic dermatitis (AD) is a chronic inflammatory skin disease which has a complex etiology that encompasses immunologic responses. The study was carried out to examine the effect of Nelumbo nucifera (Gaertn.) leaf (NL) on the AD-like skin lesion induced by repeated epicutaneous application of 2,4-dinitrochlorobenzene (DNCB) on the dorsal skin of NC/Nga mice. Three different doses of NL (5, 25, and 50 mg/mice/day) were administered orally from the day of sensitization with DNCB for 4 weeks. The efficacy of NL was judged by histopathological examination, blood IgE level, measurement of transepidermal water loss (TEWL), scratching behavior, and skin severity score. NL resulted in the suppression of clinical severity score, TEWL, scratching behavior, and blood IgE level. Histopathologic analyses revealed that thickening of the epidermis and mast cell degranulation was significantly reduced in NL group. These results suggest that NL may be a useful natural resource for the management of AD.
To evaluate the diagnostic accuracy of a new ultrasound (US) classification system for differentiating between benign and malignant solid thyroid nodules.
Materials and Methods
In this study, we enrolled 191 consecutive patients who received real-time US and subsequent US diagnoses for solid thyroid nodules, and underwent US-guided fine-needle aspiration. Each thyroid nodule was prospectively classified into 1 of 5 diagnostic categories by real-time US: "malignant," "suspicious for malignancy," "borderline," "probably benign," and "benign". We evaluated the diagnostic accuracy of thyroid US and the cut-off US criteria by comparing the US diagnoses of thyroid nodules with cytopathologic results.
Of the 191 solid nodules, 103 were subjected to thyroid surgery. US categories for these 191 nodules were malignant (n = 52), suspicious for malignancy (n = 16), borderline (n = 23), probably benign (n = 18), and benign (n = 82). A receiver-operating characteristic curve analysis revealed that the US diagnosis for solid thyroid nodules using the 5-category US classification system was very good. The sensitivity, specificity, positive and negative predictive values, and accuracy of US diagnosis were 86%, 95%, 91%, 92%, and 92%, respectively, when benign, probably benign, and borderline categories were collectively classified as benign (negative).
The diagnostic accuracy of thyroid US for solid thyroid nodules is high when the above-mentioned US classification system is applied.
Thyroid nodule; Solid, Ultrasound; Fine-needle aspiration; Classification; Malignancy
The aim of this study was to determine the efficacy of the use of an ultrasound-guided fine-needle aspiration biopsy (US-FNAB) to diagnose thyroid nodules smaller than 5 mm in the maximum diameter and to evaluate pathological findings of small thyroid malignancies.
Materials and Methods
From May 2007 to April 2008, we evaluated the findings of US-FNABs of small thyroid nodules less than 5 mm in the maximum diameter. The cytopathological findings were retrospectively reviewed and the diagnostic performance of the use of an US-FNAB was examined in all patients.
Of 201 small thyroid nodules in 180 patients, there were 162 adequate specimens (81%). Among 180 patients, 75 patients underwent thyroid surgery and 50 malignant and 33 benign nodules were identified based on a pathological examination. All small malignant thyroid nodules were identified as papillary thyroid microcarcinomas (PTMCs). There were 34 (55%) true positive, 0 (0%) false positive, 23 (37%) true negative and five (8%) false negative results for malignancy after performing a first US-FNAB in 62 surgically confirmed nodules. The sensitivity (87%), specificity (100%), positive predictive value (100%), negative predictive value (82%), accuracy (92%), false positive rate (0%) and false negative rate (8%) for an US-FNAB were determined. In 23 patients with a primary PTMC, capsular invasion (9%, 2 of 23), a perithyroidal lymph node metastasis (30%, 7 of 23), the rate of multifocality (9%, 2 of 23) and bilaterality (4%, 1 of 23) were also determined.
An US-FNAB of thyroid nodules smaller than 5 mm in the maximum diameter is an effective diagnostic procedure.
Thyroid, nodule; Fine-needle biopsies; Ultrasound (US); Microcarcinoma
The multilocus sequence typing scheme used previously for phylogenetic analysis of Escherichia coli was applied to 107 clinical isolates of Shigella flexneri. DNA sequencing of 3423 bp throughout seven housekeeping genes identified eight new allele types and ten new sequence types among the isolates. S. flexneri serotypes 1-5, X and Y were clustered together in a group containing many allelic variants while serotype 6 formed a distinct group, as previously established.
The aim of present study was to design oxycodone once-a-day controlled-release (CR) tablets and to perform in vitro/in vivo characterizations. Release profiles to achieve desired plasma concentration versus time curves were established by using simulation software and reported pharmacokinetic parameters of the drug. Hydroxypropyl methylcellulose (HPMC) 100,000 mPa·s was used as a release modifier because the polymer was found to be resistant to changes in conditions of the release study, including rotation speed of paddle and ion strength. The burst release of the drug from the CR tablets could be suppressed by applying an additional HPMC layer as a physical barrier. Finally, the oxycodone once-a-day tablet was comprised of two layers, an inert HPMC layer and a CR layer containing drug and HPMC. Commercial products, either 10 mg bis in die (bid [twice a day]) or once-a-day CR tablets (20 mg) were administered to healthy volunteers, and calculated pharmacokinetic parameters indicated bioequivalence of the two different treatments. The findings of the present study emphasize the potential of oxycodone once-a-day CR tablets for improved patient compliance, safety, and efficacy, which could help researchers to develop new CR dosage forms of oxycodone.
pharmacokinetics; oral delivery; in vitro–in vivo correlation; double-layer tablet
Asian patients with chronic myeloid leukemia (CML) tend to have different characteristics compared with patients from other regions, including younger age and smaller body size. The phase 3, open-label, randomized DASISION trial (NCT00481247), comparing dasatinib 100 mg once daily (QD) (n = 259) with imatinib 400 mg QD (n = 260) in newly diagnosed chronic phase CML (CML-CP), included a sizeable East Asian population (n = 60: dasatinib; n = 48: imatinib). In East Asian patients, dasatinib showed favorable 24-month rates of major molecular response (68% vs. 50% for imatinib) and complete cytogenetic response (92% vs. 88%), and more patients achieved BCR–ABL1 transcript levels ≤ 10% at 3 months with dasatinib (91% vs. 69%), similar to the overall population. Relative to non-East Asian patients, the incidence of rash, fluid-related events and grade 3/4 neutropenia and thrombocytopenia appeared to be higher in East Asians, regardless of treatment. Pharmacokinetic analysis revealed statistically non-significant increased dasatinib exposure among East Asian patients. Results support the use of dasatinib 100 mg QD as first-line CML treatment in both East Asian and non-East Asian patients.
CML; dasatinib; imatinib; East Asian; first-line treatment
MicroRNA (miRNA) pathways have been implicated in stem cell regulation. This study investigated the molecular effects of propofol on adipocyte stem cells (ASCs) by analyzing RNA expression arrays. Human ASCs were isolated by use of a liposuction procedure. ASCs were treated with saline, 50 µM propofol, or 100 µM propofol in culture media for 3 hours. After the isolation of total RNA, the expression of 76 miRNAs was evaluated with peptide nucleic acid-miRNA array analysis through denaturation and hybridization processes. Treatment with 50 µM propofol resulted in significant down-regulation of expression of 18 miRNAs and upregulation of expression of 25 miRNAs; 100 µM propofol resulted in significant downregulation of expression of 14 miRNAs and upregulation of expression of 29 miRNAs. The lowest expression was seen for miR-204, which was 0.07-fold with 50 µM propofol and 0.18-fold with 100 µM propofol. The highest expression was seen for miR-208b, which was 11.23-fold with 50 µM propofol and 11.20-fold with 100 µM propofol. Expression patterns of miRNAs were not significantly different between 50 µM and 100 µM propofol treatment. The results of this study suggest that propofol is involved in altering the miRNA expression level in human ASCs. Additional research is necessary to establish the functional effect of miRNA alteration by propofol.
microRNA; Propofol; Stem cell
Reversible focal lesions on the splenium of the corpus callosum (SCC) have been reported in patients with mild encephalitis/encephalopathy caused by various infectious agents, such as influenza, mumps, adenovirus, Varicella zoster, Escherichia coli, Legionella pneumophila, and Staphylococcus aureus. We report a case of a reversible SCC lesion causing reversible encephalopathy in nonfulminant hepatitis A. A 30-year-old healthy male with dysarthria and fever was admitted to our hospital. After admission his mental status became confused, and so we performed electroencephalography (EEG) and magnetic resonance imaging (MRI) of the brain, which revealed an intensified signal on diffusion-weighted imaging (DWI) at the SCC. His mental status improved 5 days after admission, and the SCC lesion had completely disappeared 15 days after admission.
Acute hepatitis A; Encephalopathy; Magnetic resonance imaging; Corpus callosum
An 81-year-old male patient was scheduled for a laparoscopic cholecystectomy due to acute cholecystitis. About 50 minutes into the operation, the arterial blood pressure suddenly decreased and ventricular fibrillation appeared on the electrocardiography. The patient received cardiopulmonary resuscitation and recovered a normal vital sign. We suspected a carbon dioxide embolism as the middle hepatic vein had been injured during the surgery. We performed a transesophageal echocardiography and were able to confirm the presence of multiple gas bubbles in all of the cardiac chambers. After the operation, the patient presented a stable hemodynamic state, but showed weaknesses in the left arm and leg. There were no acute lesions except for a chronic cerebral cortical atrophy and chronic microvascular encephalopathy on the postoperative brain-computed tomography, 3D angiography and magnetic resonance image. Fortunately, three days after the operation, the patient's hemiparesis had entirely subsided and he was discharged without any neurologic sequelae.
Carbon dioxide embolism; Cardiopulmonary resuscitation; Paradoxical embolism; Transesophageal echocardiography
Social behaviors, such as aggression or mating, proceed through a series
of appetitive and consummatory phases1 that are associated with increasing levels of
arousal2. How such
escalation is encoded in the brain, and linked to behavioral action selection,
remains an important unsolved problem in neuroscience. The ventrolateral
subdivision of the murine ventromedial hypothalamus (VMHvl) contains neurons
whose activity increases during male-male and male-female social encounters.
Non-cell type-specific optogenetic activation of this region elicited attack
behavior, but not mounting3. We
have identified a subset of VMHvl neurons marked by the estrogen receptor 1
(Esr1), and investigated their role in male social behavior. Optogenetic
manipulations indicated that Esr1+ (but not Esr1-)
neurons are sufficient to initiate attack, and that their activity is
continuously required during ongoing agonistic behavior. Surprisingly, weaker
optogenetic activation of these neurons promoted mounting behavior, rather than
attack, towards both males and females, as well as sniffing and close
investigation (CI). Increasing photostimulation intensity could promote a
transition from CI and mounting to attack, within a single social encounter.
Importantly, time-resolved optogenetic inhibition experiments revealed
requirements for Esr1+ neurons in both the appetitive
(investigative) and the consummatory phases of social interactions. Combined
optogenetic activation and calcium imaging experiments in
vitro, as well as c-Fos analysis in vivo, indicated
that increasing photostimulation intensity increases both the number of active
neurons and the average level of activity per neuron. These data suggest that
Esr1+ neurons in VMHvl control the progression of a
social encounter from its appetitive through its consummatory phases, in a
scalable manner that reflects the number or type of active neurons in the
Undifferentiated thyroid carcinoma is one of the most aggressive human cancers. Although genetic changes underlying this aggressive cancer remain to be elucidated, RAS mutations have been frequently identified in it. Mice harboring a mutant thyroid hormone receptor ThrbPV (ThrbPV/PV) spontaneously develop differentiated follicular thyroid carcinoma similar to human thyroid cancer. We recently demonstrated that targeting a RAS mutation (KrasG12D) to the thyroid of ThrbPV/PV mice (ThrbPV/PV
KrasG12D mice) promotes initiation and progression of undifferentiated thyroid cancer. To uncover genes destined to drive the aggressive cancer phenotype, we used cDNA microarrays to compare the gene expression profiles of thyroid cells of KrasG12D mice and thyroid tumor lesions of ThrbPV/PV and ThrbPV/PV
KrasG12D mice. Analyses of microarray data identified 14 upstream regulators that were significantly altered in thyroid tumors of ThrbPV/PV and ThrbPV/PV
KrasG12D mice. Most of these genes with altered expression function as key regulators in growth factor-induced signaling. Further analysis identified gene expression profiles of markedly elevated integrin levels, acting as upstream activators to stimulate ERBB2-mediated downstream signaling in thyroid tumors of ThrbPV/PV
KrasG12D mice. The present studies uncovered integrin-activated ERBB2 signaling as one of the mechanisms in synergy between TRβPV and KRASG12D signaling to promote aggressive tumor growth in undifferentiated thyroid cancer.
Growth regulation; thyroid cancer; ERBB2; integrins; microarrays; gene expression
Could nanostructures act as lenses to focus incident light for efficient utilization of photovoltaics? Is it possible, in order to avoid serious recombination loss, to realize periodic nanostructures in solar cells without direct etching in a light absorbing semiconductor? Here we propose and demonstrate a promising architecture to shape nanolenses on a planar semiconductor. Optically transparent and electrically conductive nanolenses simultaneously provide the optical benefit of modulating the incident light and the electrical advantage of supporting carrier transportation. A transparent indium-tin-oxide (ITO) nanolens was designed to focus the incident light-spectrum in focal lengths overlapping to a strong electric field region for high carrier collection efficiency. The ITO nanolens effectively broadens near-zero reflection and provides high tolerance to the incident light angles. We present a record high light-conversion efficiency of 16.0% for a periodic nanostructured Si solar cell.
Despite recent advances, understanding of molecular genetic alterations underlying thyroid carcinogenesis remains unclear. One key question is how dynamic temporal changes in global genomic expression affect carcinogenesis as the disease progresses. To address this question, we used a mouse model that spontaneously develops follicular thyroid cancer similar to human cancer (Thrb
PV/PV mice). Using complementary DNA microarrays, we compared global gene expression profiles of thyroid tumors of Thrb
PV/PV mice with the age- and gender-matched thyroids of wild-type mice at 3 weeks and at 2, 4, 6 and 14 months. These time points covered the pathological progression from early hyperplasia to capsular invasion, vascular invasion and eventual metastasis. Microarray data indicated that 462 genes were upregulated (Up-cluster genes) and 110 genes were downregulated (Down-cluster genes). Three major expression patterns (trending up, cyclical and spiking up and then down) and two (trending down and cyclical) were apparent in the Up-cluster and Down-cluster genes, respectively. Functional clustering of tumor-related genes followed by Ingenuity Pathways Analysis identified the transforming growth factor β (TGF β)-mediated network as key signaling pathways. Further functional analyses showed sustained activation of TGFβ receptor–pSMAD2/3 signaling, leading to decreased expression of E-cadherin and increased expression of fibronectin, vimentin, collagens and laminins. These TGFβ-induced changes facilitated epithelial-to-mesenchymal transition, which promotes cancer invasion and migration. Thus, complex temporal changes in gene expression patterns drive thyroid cancer progression, and persistent activation of TGFβ–TGFRβII–pSMAD2/3 signaling leads to EMT, thus promoting metastasis. This study provides new understanding of progression and metastatic spread of human thyroid cancer.
Pandemic V. cholerae strains in the O1 serogroup have 2 biotypes: classical and El Tor. The classical biotype strains of the sixth pandemic, which encode the classical type cholera toxin (CT), have been replaced by El Tor biotype strains of the seventh pandemic. The prototype El Tor strains that produce biotype-specific cholera toxin are being replaced by atypical El Tor variants that harbor classical cholera toxin. Atypical El Tor strains are categorized into 2 groups, Wave 2 and Wave 3 strains, based on genomic variations and the CTX phage that they harbor. Whole-genome analysis of V. cholerae strains in the seventh cholera pandemic has demonstrated gradual changes in the genome of prototype and atypical El Tor strains, indicating that atypical strains arose from the prototype strains by replacing the CTX phages. We examined the molecular mechanisms that effected the emergence of El Tor strains with classical cholera toxin-carrying phage. We isolated an intermediary V. cholerae strain that carried two different CTX phages that encode El Tor and classical cholera toxin, respectively. We show here that the intermediary strain can be converted into various Wave 2 strains and can act as the source of the novel mosaic CTX phages. These results imply that the Wave 2 and Wave 3 strains may have been generated from such intermediary strains in nature. Prototype El Tor strains can become Wave 3 strains by excision of CTX-1 and re-equipping with the new CTX phages. Our data suggest that inter-chromosomal recombination between 2 types of CTX phages is possible when a host bacterial cell is infected by multiple CTX phages. Our study also provides molecular insights into population changes in V. cholerae in the absence of significant changes to the genome but by replacement of the CTX prophage that they harbor.
In this report, we suggest a genetic mechanism of how the V. cholerae atypical El Tor variants were generated from classical and prototype El Tor biotype strains. An intermediary strain, containing the CTX-1 and CTX-2 prophages, was identified among the clinical isolates that were collected in 1991, when the atypical strains emerged. This strain can be converted into various Wave 2 atypical El Tor strains by eliminating prototype components, CTX-1 and RS1. Further, new types of the CTX phage genome can be generated from the intermediary strain by inter-chromosomal recombination between CTX phages and recombination between the CTX phage and RS1. These new CTX phages can be transduced into other El Tor strains, transforming them into Wave 3 atypical strains. This is a demonstrated instance of how a single-segment-genome CTX phage re-organizes its genome through recombination between different types of phage, leading to generation of new phage variants and atypical El Tor strains.
The purpose was to assess predictive factors for outcome in patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP) treated with nilotinib after imatinib failure. Imatinib-resistant and -intolerant patients with CML-CP (n = 321) were treated with nilotinib 400 mg twice daily. Of 19 baseline patient and disease characteristics and two response end points analyzed, 10 independent prognostic factors were associated with progression-free survival (PFS). In the multivariate analysis, major cytogenetic response (MCyR) within 12 months, baseline hemoglobin ≥120 g/l, baseline basophils <4%, and absence of baseline mutations with low sensitivity to nilotinib were associated with PFS. A prognostic score was created to stratify patients into five groups (best group: 0 of 3 unfavorable risk factors and MCyR by 12 months; worst group: 3 of 3 unfavorable risk factors and no MCyR by 12 months). Estimated 24-month PFS rates were 90%, 79%, 67% and 37% for patients with prognostic scores of 0, 1, 2 and 3, respectively (no patients with score of 4). Even in the presence of poor disease characteristics, nilotinib provided significant clinical benefit in patients with imatinib-resistant or -intolerant CML. This system may yield insight on the prognosis of patients.
chronic myeloid leukemia; nilotinib; multivariate analysis; predictive model; imatinib intolerance; imatinib resistance
Proteinuria is a target for renoprotection in kidney diseases. However, optimal level of proteinuria reduction in IgA nephropathy (IgAN) is unknown.
We conducted a retrospective observational study in 500 patients with biopsy-proven IgAN. Time-averaged proteinuria (TA-P) was calculated as the mean of every 6 month period of measurements of spot urine protein-to-creatinine ratio. The study endpoints were a 50% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease (ESRD), and slope of eGFR.
During a median follow-up duration of 65 (12–154) months, a 50% decline in eGFR occurred in 1 (0.8%) patient with TA-P of <0.3 g/g compared to 6 (2.7%) patients with TA-P of 0.3–0.99 g/g (hazard ratio, 2.82; P = 0.35). Risk of reaching a 50% decline in eGFR markedly increased in patients with TA-P of 1.0–2.99 g/g (P = 0.002) and those with TA-P≥3.0 g/g (P<0.001). ESRD did not occur in patients with TA-P<1.0 g/g compared to 26 (20.0%) and 8 (57.1%) patients with TA-P of 1.0–2.99 and ≥3.0 g/g, respectively. Kidney function of these two groups deteriorated faster than those with TA-P<1.0 g/g (P<0.001). However, patients with TA-P of 0.3–0.99 g/g had a greater decline of eGFR than patients with TA-P<0.3 g/g (−0.41±1.68 vs. −0.73±2.82 ml/min/1.73 m2/year, P = 0.03).
In this study, patients with TA-P<1.0 g/g show favorable outcomes. However, given the faster eGFR decline in patients with TA-P of 0.3–0.99 g/g than in patients with TA-P<0.3 g/g, the ultimate optimal goal of proteinuria reduction can be lowered in the management of IgAN.