Thermoelectric signature of quantum critical phase in a doped spin-liquid candidate.

Quantum spin liquid is a nontrivial magnetic state of longstanding interest, in which spins are strongly correlated and entangled but do not order; further intriguing is its doped version, which possibly hosts strange metal and unconventional superconductivity. A promising candidate of the doped spin liquid is a triangular-lattice organic conductor, κ-(BEDT-TTF)4Hg2.89Br8, recently found to hold metallicity, spin-liquid-like magnetism, and BEC-like superconductivity. The nature of the metallic state with the spin-liquid behaviour is awaiting to be further clarified. Here, we report the thermoelectric signature that mobile holes in the spin liquid background are in a quantum critical state and it pertains to the BEC-like superconductivity. The Seebeck coefficient divided by temperature, S/T, is enhanced on cooling with logarithmic divergence indicative of quantum criticality. Furthermore, the logarithmic enhancement is correlated with the superconducting transition temperature under pressure variation, and the temperature and magnetic field profile of S/T upon the superconducting transition change with pressure in a consistent way with the previously suggested BEC-BCS crossover. The present results reveal that the quantum criticality in a doped spin liquid emerges in a phase, not at a point, and is involved in the unconventional BEC-like nature.

Structural origins of the unusual thermal stability of amorphous CuxGe50-xTe50(0⩽x⩽33.3).

We have investigated the local atomic structures of several compositions of the amorphous phase of the system CuxGe50-xTe50(0⩽x⩽33.3), based on extended x-ray absorption fine-structure as well as anomalous x-ray scattering experiments, and discuss the unusual trend regarding their thermal stability as a function of the Cu content. At low concentrations (x⩽15), Cu atoms tend to agglomerate in flat nanoclusters reminiscent of the crystalline phase of metallic Cu, leading to a more and more Ge-deficient Ge-Te host network structure with growing Cu content and an increasing thermal stability. At higher Cu concentrations (x⩾25), Cu is incorporated into the network, leading to an overall weaker bonding situation which is associated with a decreasing thermal stability.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis treatment and follow-up of patients with localised colon cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of localised colon cancer was published in 2020. It was decided by both the ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special virtual guidelines meeting in March 2021 to adapt the ESMO 2020 guidelines to take into account the ethnic differences associated with the treatment of localised colon cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with localised colon cancer representing the oncological societies of Japan (JSMO), China (CSCO), India (ISMPO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug availability and reimbursement situations in the different Asian countries.

JSCO-ESMO-ASCO-JSMO-TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions.

A Japan Society of Clinical Oncology (JSCO)-hosted expert meeting was held in Japan on 27 October 2019, which comprised experts from the JSCO, the Japanese Society of Medical Oncology (JSMO), the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Taiwan Oncology Society (TOS). The purpose of the meeting was to focus on what we have learnt from both microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarkers in predicting the efficacy of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy, and the neurotrophic tyrosine receptor kinase (NTRK) gene fusions in predicting the efficacy of inhibitors of the tropomyosin receptor kinase (TRK) proteins across a range of solid tumour types. The recent regulatory approvals of the anti-PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib, based on specific tumour biomarkers rather than specific tumour type, have heralded a paradigm shift in cancer treatment approaches. The purpose of the meeting was to develop international expert consensus recommendations on the use of such tumour-agnostic treatments in patients with solid tumours. The aim was to generate a reference document for clinical practice, for pharmaceutical companies in the design of clinical trials, for ethics committees in the approval of clinical trial protocols and for regulatory authorities in relation to drug approvals, with a particular emphasis on diagnostic testing and patient selection.

A randomized, open-label, controlled trial of monthly oral minodronate or semiannual subcutaneous injection of denosumab for bone loss by androgen deprivation in Asian men with prostate cancer: the PRevention of Osteopenia with Minodronate And DEnosumab (PROMADE) study.

There is still a lack of evidence that minodronate or denosumab prevents bone loss due to androgen deprivation therapy (ADT) in non-Western patients. This study showed that both drugs significantly improved lumbar spine and total hip bone mineral density in Asian men with prostate cancer who received ADT. INTRODUCTION: To evaluate whether monthly oral minodronate or semiannual subcutaneous injection of denosumab improves bone mineral density (BMD) in Asian men with prostate cancer (PCa) receiving ADT. METHODS: A multicenter, open-label, randomized, controlled study including patients with hormone-sensitive PCa without bone metastasis receiving ADT was performed. Patients were randomized (1:1:1) to minodronate, denosumab, or no agent control groups. The primary end point was the mean percentage change in BMD at the lumbar spine at 12 months. Secondary end points were the mean percentage change in BMD at the femoral neck and total hip and changes in bone turnover markers. Statistical comparison was performed using analysis of covariance. RESULTS: Of the 147 subjects enrolled in this study, 102 were randomly assigned into the minodronate (n = 36), denosumab (n = 36), and control (n = 30) groups. The percentage change in BMD at the lumbar spine was significantly improved in the minodronate (2.5%, p < 0.05) and denosumab groups (4.0%, p < 0.01) compared with that in the control group (- 0.1%). Denosumab increased BMD at the femoral neck and total hip at 12 months, whereas minodronate only increased BMD at the total hip compared with controls (all p < 0.05). The percentage change in bone turnover markers at 12 months was significantly lower in the minodronate and denosumab groups compared with that in the control group (both p < 0.01). CONCLUSION: Minodronate or denosumab can be used for preventing bone loss related to ADT in Asian patients with PCa.

PRDM14 promotes malignant phenotype and correlates with poor prognosis in colorectal cancer.

BACKGROUND: Emerging evidence suggests that stemness in cancer cells is a cause of drug resistance or metastasis and is an important therapeutic target. PR [positive regulatory domain I-binding factor 1 (PRDI-BF1) and retinoblastoma protein-interacting zinc finger gene (RIZ1)] domain containing 14 (PRDM14), that regulates pluripotency in primordial germ cell, has reported the overexpression and function of stemness in various malignancies, suggesting it as the possible therapeutic target. However, to our knowledge, there have been no reports on the expression and function of PRDM14 in colorectal cancer (CRC). Therefore, we investigated the expression and the role of PRDM14 in CRC. METHODS: We performed immunohistochemistry evaluations and assessed PRDM14 expression on 414 primary CRC specimens. Colon cancer cell lines were subjected to functional and stemness assays in vitro and in vivo. RESULTS: We found that PRDM14 positive staining exhibited heterogeneity in the CRC primary tumor, especially at the tumor invasion front. The aberrant expression of PRDM14 at the invasion front was associated with lymph node metastasis and disease stage in patients with CRC. Furthermore, the multivariate analysis revealed high PRDM14 expression as an independent prognostic factor in the patients with Stage III CRC. Overexpression of PRDM14 enhanced the invasive, drug-resistant and stem-like properties in colon cancer cells in vitro and tumorigenicity in vivo. CONCLUSION: Our findings suggest that PRDM14 is involved in progression and chemoresistance of CRC, and is a potential prognostic biomarker and therapeutic target in the CRC patients.

Evaluation of Cytopathological Techniques for the Diagnosis of Canine Visceral Leishmaniosis with Lymph Node Samples.

The identification of the parasite in cytological smears of lymph node aspirates is a widely applied technique for the direct diagnosis of Leishmania spp. infection, especially in endemic areas. Although very specific, this method has limited sensitivity, and improving the technique would be highly desirable. This study aimed to evaluate the efficacy of conventional smear cytology (SC), liquid-based cytology (LBC), cell block (CB) stained with haematoxylin and eosin (HE) and immunocytochemistry (ICC), and formalin-fixed paraffin wax-embedded tissue immunohistochemistry (FFPE-IHC) compared with serology and polymerase chain reaction for the diagnosis of canine visceral leishmaniosis (CVL) in lymphoid tissue. The use of a preservative medium and centrifugation for cytological samples reduced the number of unsatisfactory artefacts/background. Moreover, LBC allowed excellent cellular preservation and the application of ancillary techniques, such as CB and ICC. SC was the most accurate morphological diagnostic method (45.0%). CB-ICC alone or associated with SC demonstrated significantly higher sensitivity (70.0% and 72.0%, respectively) when compared with SC alone (34.00%). CB-ICC was found to be more effective in the detection of infected animals with mild clinical signs, similar to FFPE-IHC. The specificity and positive predictive value were similar between all methods. Finally, the detection limit for CB-ICC and SC + CB-ICC was identical (18.46 amastigotes/mm2). Our study suggests that CB-ICC is a promising tool for improvement of the cytopathological diagnosis of CVL and may be applied in routine epidemiological screening.

Phosphorylation of GATA4 serine 105 but not serine 261 is required for testosterone production in the male mouse.

BACKGROUND: GATA4 is a transcription factor essential for male sex determination, testicular differentiation during fetal development, and male fertility in the adult. GATA4 exerts part of its function by regulating multiple genes in the steroidogenic enzyme pathway. In spite of these crucial roles, how the activity of this factor is regulated remains unclear. OBJECTIVES: Studies in gonadal cell lines have shown that GATA4 is phosphorylated on at least two serine residues-serine 105 (S105) and serine 261 (S261)-and that this phosphorylation is important for GATA4 activity. The objective of the present study is to characterize the endogenous role of GATA4 S105 and S261 phosphorylation in the mouse testis. MATERIALS AND METHODS: We examined both previously described GATA4 S105A mice and a novel GATA4 S261A knock-in mouse that we generated by CRISPR/Cas9 gene editing. The male phenotype of the mutants was characterized by assessing androgen-dependent organ weights, hormonal profiles, and expression of multiple testicular target genes using standard biochemical and molecular biology techniques. RESULTS: The fecundity of crosses between GATA4 S105A mice was reduced but without a change in sex ratio. The weight of androgen-dependent organs was smaller when compared to wild-type controls. Plasma testosterone levels showed a 70% decrease in adult GATA4 S105A males. This decrease was associated with a reduction in Cyp11a1, Cyp17a1, and Hsd17b3 expression. GATA4 S261A mice were viable and testis morphology appeared normal. Testosterone production and steroidogenic enzyme expression were not altered in GATA4 S261A males. DISCUSSION AND CONCLUSION: Our analysis showed that blocking GATA4 S105 phosphorylation is associated with decreased androgen production in males. In contrast, S261 phosphorylation by itself is dispensable for GATA4 function. These results confirm that endogenous GATA4 action is essential for normal steroid production in males and that this activity requires phosphorylation on at least one serine residue.

Site-specific Chemotherapy Based on Predicted Primary Site by Pathological Profile for Carcinoma of Unknown Primary Site.

AIMS: Although platinum-based combination chemotherapies are commonly used for unfavourable subsets of cancer of unknown primary (CUP), the prognosis remains poor. Several studies have suggested that gene expression profiling or immunohistochemistry was useful for the prediction of primary sites in CUP, and site-specific therapy based on predicted primary sites might improve overall outcomes. In Japan, to identify primary sites, immunohistochemical tests were commonly used for CUP in clinical practice. However, it is unclear whether site-specific therapy based on predicted primary sites by pathological examination contributes survival benefit for unfavourable CUP subsets. PATIENTS AND METHODS: In this study, 122 patients with unfavourable subsets of CUP were retrospectively reviewed. Ninety patients assigned to cohort A after July 2012 had received chemotherapy according to predicted primary sites; 32 patients assigned to cohort B before June 2012 had received platinum-based empiric chemotherapy. RESULTS: In cohort A, 56 patients (62.2%) with predicted primary sites by pathological examination received site-specific therapy; 34 patients (37.8%) with unpredictable primary sites received platinum-based empiric chemotherapy, the same as cohort B. The median overall survival was 20.3 months in patients with predictable primary sites in cohort A and 10.7 months in those of cohort B, with a significant difference between these cohorts (P = 0.03, adjusted hazard ratio = 0.57, 95% confidence interval 0.34-0.94). CONCLUSION: Site-specific therapy based on predicted primary sites by pathological examination could improve prognosis in patients with an unfavourable subset of CUP.

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study.

Background: Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies. Patients and methods: Eligible patients (Eastern Cooperative Oncology Group performance status 0-1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review. Results: From October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n = 384; placebo n = 381). Median follow-up was 13.4 months (interquartile range 11.1-15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86-1.19; P = 0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49-0.69; P < 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%). Conclusions: The study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated. ClinicalTrials.gov number: NCT02149108 (LUME-Colon 1).

Development of an oesophageal stimulation method to elicit swallowing reflex in humans.

Swallowing reflex is known to be evoked by gastroesophageal regurgitation or oesophageal stimulation in animal studies. However, details regarding the stimulating material, bolus size and stimulation area remain unclear for the stimulation-induced type of swallowing reflex in humans. Here, we evaluated the effects of different kinds of stimulation via water and air injection of the oesophagus on the initiation of the swallowing reflex. Nine healthy individuals participated in this study. A fibre-optic endoscope was passed transnasally, and a thin catheter for injection was passed through the other side. The tip of the catheter was placed at the upper, upper middle, lower middle or lower region of the oesophagus, and the rate of injection was controlled at 0.2 mL/s. Swallowing reflex latency was calculated as the time from injection via air or thin/thick fluid until the onset of white-out in endoscopic images. Reflex latency was significantly shorter when injection occurred at the upper region of the oesophagus than at the lower region, for both thin and thick fluids (P < .01). At the upper region of the oesophagus, the latency was significantly shorter after injection of thin fluid than with thick fluid (P < .05). Injection of air did not induce the swallowing reflex at all sites. These findings suggest that while the swallowing reflex is evoked by stimulation via fluid injection of the oesophagus in humans, sensitivity is greatest in the upper region of the oesophagus compared with the lower region and can vary depending on the injecting material.

Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (Chinese Society of Clinical Oncology), Korea (Korean Association for Clinical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology) and Taiwan (Taiwan Oncology Society). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Digitised evaluation of speech intelligibility using vowels in maxillectomy patients.

Among the functional disabilities that patients face following maxillectomy, speech impairment is a major factor influencing quality of life. Proper rehabilitation of speech, which may include prosthodontic and surgical treatments and speech therapy, requires accurate evaluation of speech intelligibility (SI). A simple, less time-consuming yet accurate evaluation is desirable both for maxillectomy patients and the various clinicians providing maxillofacial treatment. This study sought to determine the utility of digital acoustic analysis of vowels for the prediction of SI in maxillectomy patients, based on a comprehensive understanding of speech production in the vocal tract of maxillectomy patients and its perception. Speech samples were collected from 33 male maxillectomy patients (mean age 57.4 years) in two conditions, without and with a maxillofacial prosthesis, and formant data for the vowels /a/,/e/,/i/,/o/, and /u/ were calculated based on linear predictive coding. The frequency range of formant 2 (F2) was determined by differences between the minimum and maximum frequency. An SI test was also conducted to reveal the relationship between SI score and F2 range. Statistical analyses were applied. F2 range and SI score were significantly different between the two conditions without and with a prosthesis (both P < .0001). F2 range was significantly correlated with SI score in both the conditions (Spearman's r = .843, P < .0001; r = .832, P < .0001, respectively). These findings indicate that calculating the F2 range from 5 vowels has clinical utility for the prediction of SI after maxillectomy.

Evaluation of swallowing ability using swallowing sounds in maxillectomy patients.

Maxillectomy for oral tumours often results in debilitating oral hypofunction, which markedly decreases quality of life. Dysphagia, in particular, is one of the most serious problems following maxillectomy. This study used swallowing sounds as a simple evaluation method to evaluate swallowing ability in maxillectomy patients with and without their obturator prosthesis placed. Twenty-seven maxillectomy patients (15 men, 12 women; mean age 66.0 ± 12.1 years) and 30 healthy controls (14 men, 16 women; mean age 44.9 ± 21.3 years) were recruited for this study. Participants were asked to swallow 4 mL of water, and swallowing sounds were recorded using a throat microphone. Duration of the acoustic signal and duration of peak intensity (DPI) were measured. Duration of peak intensity was significantly longer in maxillectomy patients without their obturator than with it (P < .05) and was significantly longer in maxillectomy patients without their obturator than in healthy controls (P < .025 after Bonferroni correction). With the obturator placed, DPI was significantly longer in maxillectomy patients who had undergone soft palate resection than in those who had not (P < .05). These results suggest swallowing ability in maxillectomy patients could be improved by wearing an obturator prosthesis, particularly during the oral stage. However, it is difficult to improve the oral stage of swallowing in patients who have undergone soft palate resection even with obturator placement.

Prolonged lymphocytopenia after bendamustine therapy in patients with relapsed or refractory indolent B-cell and mantle cell lymphoma.

This corrects the article DOI: 10.1038/bcj.2015.86.

Factors Associated With the Development of Sarcopenia in Kidney Transplant Recipients.

INTRODUCTION: Sarcopenia is characterized by an involuntary loss of skeletal muscle mass, strength, and function. Previous studies suggest that it is generally associated with aging and chronic kidney diseases. The focus of this study was on the association between sarcopenia and pre-sarcopenia in kidney transplant recipients. METHODS: Fifty-one patients who underwent kidney transplantation at Kansai Medical University Hospital were enrolled, and their sarcopenia status was evaluated between April and July 2016. Sarcopenia was defined according to the criteria for the Asia Working Group for Sarcopenia. Skeletal muscle mass index was measured by using dual-energy radiograph absorptiometry; the cutoff points were <7.0 kg/m2 for male subjects and <5.4 kg/m2 for female subjects. For hand grip strength, values <26 kg (male subjects) and <17 kg (female subjects) was judged as sarcopenia. In both sexes, the cutoff point for walking speed was <0.8 m/s. RESULTS: Fifty-one recipients (36 men and 15 women) who met the inclusion criteria were enrolled in the study. The mean age of the recipients was 46.2 ± 12.8 years, and the mean duration of dialysis was 2.72 ± 3.61 years. Overall, 6 recipients (11.8%) had sarcopenia, and 25 recipients (49.0%) had pre-sarcopenia; 20 (39.2%) did not have sarcopenia. There were significant differences in age, duration of dialysis, body mass index, and triglyceride levels between the subgroups of recipients with and without sarcopenia. Multivariate regression analysis showed that age and duration of dialysis were independent variables for sarcopenic status. CONCLUSIONS: Our observations indicate that age and duration of dialysis before transplantation were independent determinants of sarcopenia and pre-sarcopenia in these kidney transplant recipients.

Expression of hOvol2 in the XY body of human spermatocytes.

Male infertility is common at infertile clinics, and 10-20% of infertile males are azoospermic. Non-obstructive azoospermia is a complex multifactorial disease, and the process of spermatogenesis remains largely unknown. Ovol1 and Ovol2, a family of zinc finger transcription factors, are expressed in spermatocytes at the pachytene stage and are suggested to be critical regulators of pachytene progression in male germ cells. In this study, we examined the expression of human Ovol2 (hOvol2) in the seminiferous tubes of patients subjected to testicular sperm extraction. We first cloned hOvol1 and hOvol2 from the testis of one of the patients and found no alteration in these nucleotide sequences of this patient. While hOvol1 and hOvol2 were detected by RT-PCR in the testis of patients capable of spermatogenesis, they were not detected in those with Sertoli cell-only syndrome. We recently succeeded in preparing anti-Ovol2 antibody by immunising rats with recombinant mouse Ovol2 (mOvol2) and confirmed the specificity and cross-reactivity of this antibody with hOvol2 in cells transfected with hOvol1 or hOvol2 cDNA. hOvol2 expression was restricted to the XY body of spermatocytes at the pachytene stage. This study demonstrates that hOvol2 is expressed in germ cells and may be involved in spermatogenesis.

Relationship between volume of the seminal vesicles and sexual activity in middle-aged men.

The relationship between volume of the seminal vesicles and the frequency of sex and sexual function in middle-aged men is not clear. This study included 81 patients who were diagnosed with localized prostate cancer. Volume of the seminal vesicles was examined using a volume analyser from computed tomography. Sexual function was subjectively evaluated using the Expanded Prostate Cancer Index Composite and Erection Hardness Score. The frequency of sex was surveyed using our original questionnaire. The mean ± SD age of the patients was 67.7 ± 5.3 years. There was no relationship between the volume of seminal vesicles and age of the patients. Volume of the seminal vesicles in patients who answered that they had sexual activity at least once a year was significantly larger than in those who answered no sexual activity for several years (P < .01) Moreover, among sexually active, middle-aged men, volume of the seminal vesicles was significantly larger in those who had a sexual frequency once every 3 months than in those who had a sexual frequency once every 6 months or once a year (P < .05). Our study suggests that the volume of seminal vesicles of middle-aged men is correlated with sexual activity.